Novel pyridopyrimidine derivatives and use thereof

ABSTRACT

The invention provides novel substituted pyridopyrimidines represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of the phosphoinositide 3′ OH kinase family (PI3K) for the treatment of inflammatory diseases, cancer, cardiovascular diseases, allergy, asthma and autoimmune disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the priority to Application No. 61/453,850 filedon Mar. 17, 2011, which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to a series of substituted pyridopyrimidine whichare kinase inhibitors, especially inhibitors of the phosphoinositide 3′OH kinase family (hereinafter PI3 Kinase; PI3Kα, PI3Kβ, PI3Kγ and/orPI3Kδ) for treatment of inflammatory diseases, cancer, cardiovasculardiseases, allergy, asthma and autoimmune disorders. This invention alsorelates to a pharmaceutical composition comprising the compound of theinvention, use of the compound in the preparation of a medicament, andmethod of treatment for hyperproliferative diseases in mammals,especially humans by administering the compound thereof.

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) are a family of enzymes involvedin cellular function such as cell growth, proliferation,differentiation, motility, survival and intracellular trafficking, whichin turn are involved in cancer. And the PI3Ks utilize both lipid andprotein kinase activity to regulate numerous intracellular signaltransduction pathway, which in turn coordinate a range of downstreamcellular processes.

The PI3K family is divided into three classes (I, II, and III). Theclassifications are based on primary structure, regulation, and in vitrolipid substrate specificity. Class I PI3Ks have received the mostattention from the scientific community and are further broken down intotwo subclasses, 1A and 1B, which are responsible for the production ofPhosphatidylinositol 3-phosphate (PI(3)P), Phosphatidylinositol(3,4)-bisphosphate (PI(3,4)P₂), and Phosphatidylinositol(3,4,5)-trisphosphate (PI(3,4,5)P₃) (Vanhaesebroeck et al., TrendsBiochem. Sci., 1997, 22(7), 267-272.; Leslie et al., Chem. Rev., 2001,101(8), 2365-2380) (FIG. 1).

The class IA isoforms, PI3Kα, PI3Kβ, and PI3Kδ, are primarily activatedby protein tyrosine kinase-coupled receptors, whereas the sole class IBmember, PI3Kγ is activated by G-protein coupled receptors (GPCRs), suchas chemokine receptors (Leevers S J et al., Current Opinion in CellBiology 1999, 11(2) 219-225). Class IA PI3K is composed of a heterodimerbetween a p110 catalytic subunit and a p85 regulatory subunit (CarpenterC L et al., J. Biol. Chem. 1990, 265 (32), 19704-19711). There are fivevariants of the p85 regulatory subunit, designated p85α, p55α, p50α,p85β, or p55γ. There are also three variants of the p110 catalyticsubunit designated p110α, β, or δ catalytic subunit. The first threeregulatory subunits are all splice variants of the same gene (Pik3r1),the other two being expressed by other genes (Pik3r2 and Pik3r3, p85β,and p55γ, respectively). The most highly expressed regulatory subunit isp85α; all three catalytic subunits are expressed by separate genes(Pik3ca, Pik3cb, and Pik3cd for p110α, p110β, and p110δ, respectively).The first two p110 isoforms (α and β) are expressed in all cells, butp110δ is expressed primarily in leukocytes, and it has been suggestedthat it evolved in parallel with the adaptive immune system. Theregulatory p101 and unique catalytic p110γ subunits comprise the type IBPI3K and are encoded by a single gene each. Each isoforms have unfoldedthe close connections between PI3Kα with oncogenesis, PI3Kβ withthrombosis, PI3Kδ with immune function and PI3Kγ with inflammation bypathophysiologic studies. Class II PI3Ks include PI3K C2a, C2p and C2ysubtypes, which are characterized by containing C2 domains at the Cterminus. The substrate for class III PI3Ks is PI only.

Wortmannin and LY294002 are well known and studied as a first generationPI3K inhibitor. Wortmannin was first isolated from Penicillium wortmanniin 1957 (Brian, P. W. et al., Bri. Mycol. Soc., 1957, 40, 365-368), butthe structure was recognized in 1974 (Wiesinger, D. et al., Cell Mol.Life. Sci., 1974, 30, 135-136). It was reported for theanti-inflammatory activity (Wiesinger, D. et al, Experintia, 1974, 30,135-136) and identified as a PI3K inhibitor (Powis, G. et al., CancerRes., 1994, 54, 2419-2423). LY294002 is the first synthetic PI3Kinhibitor with a quercetin modified chemical structure. LY294002 wafirst described as a competitive PI3K inhibitor in 1994 (Vlahos, C. J.et al., J. Biol. Chem., 1994, 269, 5241-5248).

Compounds suitable as PI3K inhibitors are also disclosed in WO07/044,729; WO 08/152,390; WO 08/070,740; WO 09/039,140; WO 09/052,145;WO 09/143,317; WO 10/002,954; WO 10/037,765; WO 10/091,996; WO10/100,144; WO 10/135,014; WO 10/144,513; WO 10/102,958; WO 10/133,318and WO 10/007,099.

SUMMARY OF THE INVENTION

This invention provides for novel heterocyclic a compound of formula Ior a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof:

wherein

X is C or O or N or S; Y is C or N;

R₁ is selected from the group consisting of acyl, amino, substitutedamino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substitutedC3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl,heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl,arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substitutedheteroarylalkyl, cyano, nitro;R₂ is selected from the group consisting of hydrogen, halogen, acyl,amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl,C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl, C3-7Cheterocycloalkyl,substituted C3-C7heterocycloalkyl, alkylcarboxy, arylamino, aryl,substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl,heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro, alkoxy,C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy,C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy, acyloxy,aryloxy;R₃═NR_(4′)SO₂R_(4′)SO₂NR_(4′)R₄, NR_(4′)COR₄, CONR_(4′)R₄,NR_(4′)CONHR₄;R₄ is selected from the group consisting of: alkyl, substituted alkyl,amino, halo, C3-C7cycloalkyl, substituted C3-C7cycloalkyl,C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl,substituted aryl, heteroaryl and substituted heteroaryl;R_(4′) is H or C1-C6 alkyl;R₅ is selected from the group consisting of: hydrogen, halogen,C1-C6alkyl;R₆ is selected from the group consisting of: hydrogen, halogen, acyl,alkoxy, amino, substituted amino, arylamino, C1-C6alkyl, substitutedC1-C6 alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl,C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl,substituted aryl, heteroaryl, and substituted heteroaryl;n is 0 or 1; m is 0 or 1;and/or a pharmaceutically acceptable salt thereof.

In other embodiments, the present invention provides compoundsrepresented by the following Formulae:

or a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.

Compounds of present invention are inhibitors of PI3K and, consequently,are useful for treating cancers and other hyperproliferative diseases.

Compounds of present invention are inhibitors of PI3K and, consequently,are also related to a method of treating one or more disease statesselected from: autoimmune disorders, inflammatory diseases, allergy,asthma, cardiovascular diseases, kidney diseases, pancreatitis,multiorgan failure and thrombosis.

In other aspects, the present invention is directed to a pharmaceuticalcomposition comprising an effective amount of a compound of formula I ora pharmaceutically acceptable salt, solvate, polymorph, ester, tautomeror prodrug thereof. In some embodiments, the pharmaceutical compositionfurther comprises a pharmaceutically acceptable carrier, adjuvantsand/or excipients. In some embodiments, such a composition may containat least one of preservatives, agents for delaying absorption, fillers,binders, adsorbents, buffers, disintegrating agents, solubilizingagents, and other carriers, adjuvants and/or excipients as inertingredients. The composition may be formulated with a method well-knownin the art.

In some aspects, the present invention is directed to a method oftreating a disease in an individual suffering from said diseasecomprising administering to said individual a therapeutically effectiveamount of a composition comprising a compound of formula I or apharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof.

In other aspects, the present invention is directed to a method oftreating a disorder in a mammal, comprising administering to said mammala therapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof.

In other aspects, the present invention is directed to a method oftreating a disorder in a human, comprising administering to said human atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof.

In other aspects, the present invention is directed to a method oftreating an inflammatory disease, condition, or disorder in a mammal,including a human, comprising administering to said mammal atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt, ester, prodrug, solvate, such ashydrate, polymorph or tautomer thereof.

In other aspects, the present invention is directed to a method oftreating a disorder or condition which is modulated by the PI3K cascadein a mammal, including a human, comprising administering to said mammalan amount of the compound of formula I or a pharmaceutically acceptablesalt, ester, prodrug, solvate, such as hydrate, polymorph or tautomerthereof, effective to modulate said cascade. The appropriate dosage fora particular patient can be determined, according to known methods, bythose skilled in the art.

In other aspects, the present invention is directed to use of compoundof formula I or a pharmaceutically acceptable salt, ester, prodrug,solvate, such as hydrate, polymorph or tautomer thereof in thepreparation of a pharmaceutical composition. The pharmaceuticalcomposition can be used for treating a disorder or condition which ismodulated by the PI3K cascade in a mammal, including a human. Thepharmaceutical composition is useful for treating cancer, inflammatorydisease and other hyperproliferative diseases.

In other aspects, the present invention is directed to a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.In some embodiments, the pharmaceutical composition is in a formsuitable for oral administration. In further or additional embodiments,the pharmaceutical composition is in the form of a tablet, capsule,pill, powder, sustained release formulation, solution and suspension. Insome embodiments, the pharmaceutical composition is in a form suitablefor parenteral injection, such as a sterile solution, suspension oremulsion; for topical administration as an ointment or cream or forrectal administration as a suppository. In further or additionalembodiments, the pharmaceutical composition is in unit dosage formssuitable for single administration of precise dosages. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.001 to about 1000 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.5 to about 50 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is about0.001 to about 7 g/day. In further or additional embodiments the amountof compound of formula I is about 0.002 to about 6 g/day. In further oradditional embodiments the amount of compound of formula I is about0.005 to about 5 g/day. In further or additional embodiments the amountof compound of formula I is about 0.01 to about 5 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.02to about 5 g/day. In further or additional embodiments the amount ofcompound of formula I is about 0.05 to about 2.5 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.1to about 1 g/day. In further or additional embodiments, dosage levelsbelow the lower limit of the aforesaid range may be more than adequate.In further or additional embodiments, dosage levels above the upperlimit of the aforesaid range may be required. In further or additionalembodiments the compound of formula I is administered in a single dose,once daily. In further or additional embodiments the compound of formulaI is administered in multiple doses, more than once per day. In furtheror additional embodiments the compound of formula I is administeredtwice daily. In further or additional embodiments the compound offormula I is administered three times per day. In further or additionalembodiments the compound of formula I is administered four times perday. In further or additional embodiments the compound of formula I isadministered more than four times per day. In some embodiments, thepharmaceutical composition is for administration to a mammal. In furtheror additional embodiments, the mammal is human. In further or additionalembodiments, the pharmaceutical composition further comprises apharmaceutical carrier, excipient and/or adjuvant. In further oradditional embodiments, the pharmaceutical composition further comprisesat least one therapeutic agent. In further or additional embodiments,the therapeutic agent is selected from the group consisting of cytotoxicagents, anti-angiogenesis agents and anti-neoplastic agents. In furtheror additional embodiments, the anti-neoplastic agent is selected fromthe group consisting of alkylating agents, anti-metabolites,epidophyllotoxins; antineopiastic enzymes, topoisomerase inhibitors,procarbazines, mitoxantrones, platinum coordination complexes,biological response modifiers and growth inhibitors,hormonal/anti-hormonal therapeutic agents, and haematopoietic growthfactors. In further or additional embodiments, the therapeutic agent istaxol, bortezomib or both. In further or additional embodiments, thepharmaceutical composition is administered in combination with anadditional therapy. In further or additional embodiments, the additionaltherapy is radiation therapy, chemotherapy or a combination of both. Infurther or additional embodiments, the pharmaceutical compositioncomprises a pharmaceutically acceptable salt of a compound of formula I.

In other aspects, the present invention is directed to a method forinhibiting a PI3K enzyme. The method comprises contacting said PI3Kenzyme with an amount of a composition comprising a compound of formulaI or a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof, sufficient to inhibit said enzyme, whereinsaid enzyme is inhibited. In some embodiments, the present invention isdirected to a method for selectively inhibiting a PI3K enzyme.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for inhibiting a PI3K enzyme.

In further or additional embodiments the enzyme is at least about 1%inhibited. In further or additional embodiments the enzyme is at leastabout 2% inhibited. In further or additional embodiments the enzyme isat least about 3% inhibited. In further or additional embodiments theenzyme is at least about 4% inhibited. In further or additionalembodiments the enzyme is at least about 5% inhibited. In further oradditional embodiments the enzyme is at least about 10% inhibited. Infurther or additional embodiments the enzyme is at least about 20%inhibited. In further or additional embodiments the enzyme is at leastabout 25% inhibited. In further or additional embodiments the enzyme isat least about 30% inhibited. In further or additional embodiments theenzyme is at least about 40% inhibited. In further or additionalembodiments the enzyme is at least about 50% inhibited. In further oradditional embodiments the enzyme is at least about 60% inhibited. Infurther or additional embodiments the enzyme is at least about 70%inhibited. In further or additional embodiments the enzyme is at leastabout 75% inhibited. In further or additional embodiments the enzyme isat least about 80% inhibited. In further or additional embodiments theenzyme is at least about 90% inhibited. In further or additionalembodiments the enzyme is essentially completely inhibited.

In other aspects, the present invention is directed to a method oftreatment of a PI3K mediated disorder in an individual suffering fromsaid disorder comprising administering to said individual an effectiveamount of a composition comprising a compound of formula I or apharmaceutically acceptable salt, solvate, polymorph, ester, tautomer orprodrug thereof.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for treating a PI3K mediated disorder.

In some embodiments, the composition comprising a compound of formula Iis administered orally, intraduodenally, parenterally (includingintravenous, subcutaneous, intramuscular, intravascular or by infusion),topically or rectally. In some embodiments, the pharmaceuticalcomposition is in a form suitable for oral administration. In further oradditional embodiments, the pharmaceutical composition is in the form ofa tablet, capsule, pill, powder, sustained release formulations,solution and suspension for oral administration, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream, or for rectal administration asa suppository. In further or additional embodiments, the pharmaceuticalcomposition is in unit dosage forms suitable for single administrationof precise dosages. In further or additional embodiments, thepharmaceutical composition further comprises a pharmaceutical carrier,excipient and/or adjuvant. In further or additional embodiments theamount of compound of formula I is in the range of about 0.001 to about1000 mg/kg body weight/day. In further or additional embodiments theamount of compound of formula I is in the range of about 0.5 to about 50mg/kg body weight/day. In further or additional embodiments the amountof compound of formula I is about 0.001 to about 7 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.01to about 7 g/day. In further or additional embodiments the amount ofcompound of formula I is about 0.02 to about 5 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.05to about 2.5 g/day. In further or additional embodiments the amount ofcompound of formula I is about 0.1 to about 1 g/day. In further oradditional embodiments, dosage levels below the lower limit of theaforesaid range may be more than adequate. In further or additionalembodiments, dosage levels above the upper limit of the aforesaid rangemay be required. In further or additional embodiments the compound offormula I is administered in a single dose, once daily. In further oradditional embodiments the compound of formula I is administered inmultiple doses, more than once per day. In further or additionalembodiments the compound of formula I is administered twice daily. Infurther or additional embodiments the compound of formula I isadministered three times per day. In further or additional embodimentsthe compound of formula I is administered four times per day. In furtheror additional embodiments the compound of formula I is administered morethan four times per day. In some embodiments, the individual sufferingfrom the PI3K mediated disorder is a mammal. In further or additionalembodiments, the individual is a human. In some embodiments, thecomposition comprising a compound of formula I is administered incombination with an additional therapy. In further or additionalembodiments, the additional therapy is radiation therapy, chemotherapyor a combination of both. In further or additional embodiments, thecomposition comprising a compound of formula I is administered incombination with at least one therapeutic agent. In further oradditional embodiments, the therapeutic agent is selected from the groupof cytotoxic agents, anti-angiogenesis agents and anti-neoplasticagents. In further or additional embodiments, the anti-neoplastic agentis selected from the group of consisting of alkylating agents,anti-metabolites, epidophyllotoxins; antineoplastic enzymes,topoisomerase inhibitors, procarbazines, mitoxantrones, platinumcoordination complexes, biological response modifiers and growthinhibitors, hormonal/anti-hormonal therapeutic agents, andhaematopoietic growth factors. In further or additional embodiments, thetherapeutic agent is selected from taxol, bortezomib or both. In someembodiments, the PI3K mediated disorder is selected from the groupconsisting of inflammatory diseases, infections, autoimmune disorders,stroke, ischemia, cardiac disorder, neurological disorders, fibrogenicdisorders, proliferative disorders, hyperproliferative disorders,non-cancer hyper-proliferative disorders, tumors, leukemias, neoplasms,cancers, carcinomas, metabolic diseases, malignant disease, vascularrestenosis, psoriasis, atherosclerosis, rheumatoid arthritis,osteoarthritis, heart failure, chronic pain, neuropathic pain, dry eye,closed angle glaucoma and wide angle glaucoma. In further or additionalembodiments, the PI3K mediated disorder is an inflammatory disease. Infurther or additional embodiments, the PI3K mediated disorder is ahyperproliferative disease. In further or additional embodiments, thePI3K mediated disorder is selected from the group consisting of tumors,leukemias, neoplasms, cancers, carcinomas and malignant disease. Infurther or additional embodiments, the cancer is brain cancer, breastcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, colorectal cancer or leukemia. In further or additionalembodiments, the fibrogenetic disorder is scleroderma, polymyositis,systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation,interstitial nephritis or pulmonary fibrosis. In further or additionalembodiments, an effective amount of a composition comprising apharmaceutically acceptable salt of a compound of formula I isadministered.

In other aspects, the present invention is directed to a method fordegrading, inhibiting the growth of or killing a cancer cell comprisingcontacting said cell with an amount of a composition effective todegrade, inhibit the growth of or to kill said cell, the compositioncomprising a compound of formula I or a pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for degrading and/or inhibiting the growth ofor killing a cancer cell.

In some embodiments, the cancer cells comprise brain, breast, lung,ovarian, pancreatic, prostate, renal, or colorectal cancer cells. Infurther or additional embodiments, the composition is administered withat least one therapeutic agent. In further or additional embodiments,the therapeutic agent is taxol, bortezomib or both. In further oradditional embodiments, the therapeutic agent is selected from the groupconsisting of cytotoxic agents, anti-angiogenesis agents andanti-neoplastic agents. In further or additional embodiments, theanti-neoplastic agents selected from the group of consisting ofalkylating agents, anti-metabolites, epidophyllotoxins; antineoplasticenzymes, topoisomerase inhibitors, procarbazines, mitoxantrones,platinum coordination complexes, biological response modifiers andgrowth inhibitors, hormonal/anti-hormonal therapeutic agents, andhaematopoietic growth factors. In some embodiments, the cancer cells aredegraded. In further or additional embodiments, 1% of the cancer cellsare degraded. In further or additional embodiments, 2% of the cancercells are degraded. In further or additional embodiments, 3% of thecancer cells are degraded. In further or additional embodiments, 4% ofthe cancer cells are degraded. In further or additional embodiments, 5%of the cancer cells are degraded. In further or additional embodiments,10% of the cancer cells are degraded. In further or additionalembodiments, 20% of the cancer cells are degraded. In further oradditional embodiments, 25% of the cancer cells are degraded. In furtheror additional embodiments, 30% of the cancer cells are degraded. Infurther or additional embodiments, 40% of the cancer cells are degraded.In further or additional embodiments, 50% of the cancer cells aredegraded. In further or additional embodiments, 60% of the cancer cellsare degraded. In further or additional embodiments, 70% of the cancercells are degraded. In further or additional embodiments, 75% of thecancer cells are degraded. In further or additional embodiments, 80% ofthe cancer cells are degraded. In further or additional embodiments, 90%of the cancer cells are degraded. In further or additional embodiments,100% of the cancer cells are degraded. In further or additionalembodiments, essentially all of the cancer cells are degraded. In someembodiments, the cancer cells are killed. In further or additionalembodiments, 1% of the cancer cells are killed. In further or additionalembodiments, 2% of the cancer cells are killed. In further or additionalembodiments, 3% of the cancer cells are killed. In further or additionalembodiments, 4% of the cancer cells are killed. In further or additionalembodiments, 5% of the cancer cells are killed. In further or additionalembodiments, 10% of the cancer cells are killed. In further oradditional embodiments, 20% of the cancer cells are killed. In furtheror additional embodiments, 25% of the cancer cells are killed. Infurther or additional embodiments, 30% of the cancer cells are killed.In further or additional embodiments, 40% of the cancer cells arekilled. In further or additional embodiments, 50% of the cancer cellsare killed. In further or additional embodiments, 60% of the cancercells are killed. In further or additional embodiments, 70% of thecancer cells are killed. In further or additional embodiments, 75% ofthe cancer cells are killed. In further or additional embodiments, 80%of the cancer cells are killed. In further or additional embodiments,90% of the cancer cells are killed. In further or additionalembodiments, 100% of the cancer cells are killed. In further oradditional embodiments, essentially all of the cancer cells are killed.In further or additional embodiments, the growth of the cancer cells isinhibited. In further or additional embodiments, the growth of thecancer cells is about 1% inhibited. In further or additionalembodiments, the growth of the cancer cells is about 2% inhibited. Infurther or additional embodiments, the growth of the cancer cells isabout 3% inhibited. In further or additional embodiments, the growth ofthe cancer cells is about 4% inhibited. In further or additionalembodiments, the growth of the cancer cells is about 5% inhibited. Infurther or additional embodiments, the growth of the cancer cells isabout 10% inhibited. In further or additional embodiments, the growth ofthe cancer cells is about 20% inhibited. In further or additionalembodiments, the growth of the cancer cells is about 25% inhibited. Infurther or additional embodiments, the growth of the cancer cells isabout 30% inhibited. In further or additional embodiments, the growth ofthe cancer cells is about 40% inhibited. In further or additionalembodiments, the growth of the cancer cells is about 50% inhibited. Infurther or additional embodiments, the growth of the cancer cells isabout 60% inhibited. In further or additional embodiments, the growth ofthe cancer cells is about 70% inhibited. In further or additionalembodiments, the growth of the cancer cells is about 75% inhibited. Infurther or additional embodiments, the growth of the cancer cells isabout 80% inhibited. In further or additional embodiments, the growth ofthe cancer cells is about 90% inhibited. In further or additionalembodiments, the growth of the cancer cells is about 100% inhibited. Infurther or additional embodiments, a composition comprising apharmaceutically acceptable salt of a compound of formula I is used.

In other aspects, the present invention is directed to a method for thetreatment or prophylaxis of a proliferative disease in an individualcomprising administering to said individual an effective amount of acomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or pro-drugthereof.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for the treatment or prophylaxis of aproliferative disease.

In some embodiments, the proliferative disease is cancer, psoriasis,restenosis, autoimmune disease, or atherosclerosis. In further oradditional embodiments, the proliferative disease is ahyperproliferative disease. In further or additional embodiments, theproliferative disease is selected from the group consisting of tumors,leukemias, neoplasms, cancers, carcinomas and malignant disease. Infurther or additional embodiments, the cancer is brain cancer, breastcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, colorectal cancer or leukemia. In further or additionalembodiments, the fibrogenetic disorder is scleroderma, polymyositis,systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation,interstitial nephritis or pulmonary fibrosis. In further or additionalembodiments, the cancer is brain cancer, breast cancer, lung cancer,ovarian cancer, pancreatic cancer, prostate cancer, renal cancer,colorectal cancer or leukemia. In further or additional embodiments, thecancer is brain cancer or adrenocortical carcinoma. In further oradditional embodiments, the cancer is breast cancer. In further oradditional embodiments, the cancer is ovarian cancer. In further oradditional embodiments, the cancer is pancreatic cancer. In further oradditional embodiments, the cancer is prostate cancer. In further oradditional embodiments, the cancer is renal cancer. In further oradditional embodiments, the cancer is colorectal cancer. In further oradditional embodiments, the cancer is myeloid leukemia. In further oradditional embodiments, the cancer is glioblastoma. In further oradditional embodiments, the cancer is follicular lymphoma. In further oradditional embodiments, the cancer is pre-B acute leukemia. In furtheror additional embodiments, the cancer is chronic lymphocytic B-leukemia.In further or additional embodiments, the cancer is mesothelioma. Infurther or additional embodiments, the cancer is small cell line cancer.In some embodiments, the composition comprising a compound of formula Iis administered in combination with an additional therapy. In further oradditional embodiments, the additional therapy is radiation therapy,chemotherapy or a combination of both. In further or additionalembodiments, the composition comprising a compound of formula I isadministered in combination with at least one therapeutic agent. Infurther or additional embodiments, the therapeutic agent is selectedfrom the group of cytotoxic agents, anti-angiogenesis agents andanti-neoplastic agents. In further or additional embodiments, theanti-neoplastic agent is selected from the group of consisting ofalkylating agents, anti-metabolites, epidophyllotoxins; antineoplasticenzymes, topoisomerase inhibitors, procarbazines, mitoxantrones,platinum coordination complexes, biological response modifiers andgrowth inhibitors, hormonal/anti-hormonal therapeutic agents, andhaematopoietic growth factors. In further or additional embodiments, thetherapeutic agent is selected from taxol, bortezomib or both. In someembodiments, the composition is administered orally, intraduodenally,parenterally (including intravenous, subcutaneous, intramuscular,intravascular or by infusion), topically or rectally. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.001 to about 1000 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.5 to about 50 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is about0.001 to about 7 g/day. In further or additional embodiments the amountof compound of formula I is about 0.01 to about 7 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.02to about 5 g/day. In further or additional embodiments the amount ofcompound of formula I is about 0.05 to about 2.5 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.1to about 1 g/day. In further or additional embodiments, dosage levelsbelow the lower limit of the aforesaid range may be more than adequate.In further or additional embodiments, dosage levels above the upperlimit of the aforesaid range may be required. In further or additionalembodiments the compound of formula I is administered in a single dose,once daily. In further or additional embodiments the compound of formulaI is administered in multiple doses, more than once per day. In furtheror additional embodiments the compound of formula I is administeredtwice daily. In further or additional embodiments the compound offormula I is administered three times per day. In further or additionalembodiments the compound of formula I is administered four times perday. In further or additional embodiments the compound of formula I isadministered more than four times per day. In some embodiments, theindividual suffering from the proliferative disease is a mammal. Infurther or additional embodiments, the individual is a human. In furtheror additional embodiments, an effective amount of a compositioncomprising a pharmaceutically acceptable salt of a compound of formula Iis administered.

In other aspects, the present invention is directed to a method for thetreatment or prophylaxis of an inflammatory disease in an individualcomprising administering to said individual an effective amount of acomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for the treatment or prophylaxis of aninflammatory disease.

In further or additional embodiments, the inflammatory disease isselected from chronic inflammatory diseases, rheumatoid arthritis,spondyloarthropathies, gouty arthritis, osteoarthritis, juvenilearthritis, acute rheumatic arthritis, enteropathic arthritis,neuropathic arthritis, psoriatic arthritis, pyogenic arthritis,atherosclerosis, systemic lupus erythematosus, inflammatory boweldisease, irritable bowel syndrome, ulcerative colitis, refluxesophagitis, Crohn's disease, gastritis, asthma, allergies, respiratorydistress syndrome, pancreatitis, chronic obstructive pulmonary disease,pulmonary fibrosis, psoriasis, eczema or scleroderma. In someembodiments, the composition comprising a compound of formula I isadministered in combination with an additional therapy. In further oradditional embodiments, the composition comprising a compound of formulaI is administered in combination with at least one therapeutic agent. Insome embodiments, the composition is administered orally,intraduodenally, parenterally (including intravenous, subcutaneous,intramuscular, intravascular or by infusion), topically or rectally. Infurther or additional embodiments the amount of compound of formula I isin the range of about 0.001 to about 1000 mg/kg body weight/day. Infurther or additional embodiments the amount of compound of formula I isin the range of about 0.5 to about 50 mg/kg body weight/day. In furtheror additional embodiments the amount of compound of formula I is about0.001 to about 7 g/day. In further or additional embodiments the amountof compound of formula I is about 0.01 to about 7 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.02to about 5 g/day. In further or additional embodiments the amount ofcompound of formula I is about 0.05 to about 2.5 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.1to about 1 g/day. In further or additional embodiments, dosage levelsbelow the lower limit of the aforesaid range may be more than adequate.In further or additional embodiments, dosage levels above the upperlimit of the aforesaid range may be required. In further or additionalembodiments the compound of formula I is administered in a single dose,once daily. In further or additional embodiments the compound of formulaI is administered in multiple doses, more than once per day. In furtheror additional embodiments the compound of formula I is administeredtwice daily. In further or additional embodiments the compound offormula I is administered three times per day. In further or additionalembodiments the compound of formula I is administered four times perday. In further or additional embodiments the compound of formula I isadministered more than four times per day. In some embodiments, theindividual suffering from the inflammatory disease is a mammal. Infurther or additional embodiments, the individual is a human. In furtheror additional embodiments, an effective amount of a compositioncomprising a pharmaceutically acceptable salt of a compound of formula Iis administered.

In other aspects, the present invention is directed to a method for thetreatment or prophylaxis of cancer in an individual comprisingadministering to said individual an effective amount of a compositioncomprising a compound of formula I or a pharmaceutically acceptablesalt, solvate, polymorph, ester, tautomer or prodrug thereof.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for the treatment or prophylaxis of a cancer.

In further or additional embodiments, the cancer is brain cancer, breastcancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer,renal cancer, colorectal cancer or leukemia. In further or additionalembodiments, the fibrogenetic disorder is scleroderma, polymyositis,systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation,interstitial nephritis or pulmonary fibrosis. In further or additionalembodiments, the cancer is brain cancer, breast cancer, lung cancer,ovarian cancer, pancreatic cancer, prostate cancer, renal cancer,colorectal cancer or leukemia. In further or additional embodiments, thecancer is brain cancer or adrenocortical carcinoma. In further oradditional embodiments, the cancer is breast cancer. In further oradditional embodiments, the cancer is ovarian cancer. In further oradditional embodiments, the cancer is pancreatic cancer. In further oradditional embodiments, the cancer is prostate cancer. In further oradditional embodiments, the cancer is renal cancer. In further oradditional embodiments, the cancer is colorectal cancer. In further oradditional embodiments, the cancer is myeloid leukemia. In further oradditional embodiments, the cancer is glioblastoma. In further oradditional embodiments, the cancer is follicular lymphoma. In further oradditional embodiments, the cancer is pre-B acute leukemia. In furtheror additional embodiments, the cancer is chronic lymphocytic B-leukemia.In further or additional embodiments, the cancer is mesothelioma. Infurther or additional embodiments, the cancer is small cell line cancer.In some embodiments, the composition comprising a compound of formula Iis administered in combination with an additional therapy. In further oradditional embodiments, the additional therapy is radiation therapy,chemotherapy or a combination of both. In further or additionalembodiments, the composition comprising a compound of formula I isadministered in combination with at least one therapeutic agent. Infurther or additional embodiments, the therapeutic agent is selectedfrom the group of cytotoxic agents, anti-angiogenesis agents andanti-neoplastic agents. In further or additional embodiments, theanti-neoplastic agent is selected from the group of consisting ofalkylating agents, anti-metabolites, epidophyllotoxins; antineoplasticenzymes, topoisomerase inhibitors, procarbazines, mitoxantrones,platinum coordination complexes, biological response modifiers andgrowth inhibitors, hormonal/anti-hormonal therapeutic agents, andhaematopoietic growth factors. In further or additional embodiments, thetherapeutic agent is selected from taxol, bortezomib or both. In someembodiments, the composition is administered orally, intraduodenally,parenterally (including intravenous, subcutaneous, intramuscular,intravascular or by infusion), topically or rectally. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.001 to about 1000 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.5 to about 50 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is about0.001 to about 7 g/day. In further or additional embodiments the amountof compound of formula I is about 0.01 to about 7 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.02to about 5 g/day. In further or additional embodiments the amount ofcompound of formula I is about 0.05 to about 2.5 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.1to about 1 g/day. In further or additional embodiments, dosage levelsbelow the lower limit of the aforesaid range may be more than adequate.In further or additional embodiments, dosage levels above the upperlimit of the aforesaid range may be required. In further or additionalembodiments the compound of formula I is administered in a single dose,once daily. In further or additional embodiments the compound of formulaI is administered in multiple doses, more than once per day. In furtheror additional embodiments the compound of formula I is administeredtwice daily. In further or additional embodiments the compound offormula I is administered three times per day. In further or additionalembodiments the compound of formula I is administered four times perday. In further or additional embodiments the compound of formula I isadministered more than four times per day. In some embodiments, theindividual suffering from cancer is a mammal. In further or additionalembodiments, the individual is a human. In further or additionalembodiments, an effective amount of a composition comprising apharmaceutically acceptable salt of a compound of formula I isadministered.

In other aspects, the present invention is directed to a method ofreducing the size of a tumor, inhibiting tumor size increase, reducingtumor proliferation or preventing tumor proliferation in an individual,comprising administering to said individual an effective amount of acomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for reducing the size of a tumor, inhibitingtumor size increase, reducing tumor proliferation or preventing tumorproliferation.

In some embodiments, the size of a tumor is reduced. In further oradditional embodiments, the size of a tumor is reduced by at least 1%.In further or additional embodiments, the size of a tumor is reduced byat least 2%. In further or additional embodiments, the size of a tumoris reduced by at least 3%. In further or additional embodiments, thesize of a tumor is reduced by at least 4%. In further or additionalembodiments, the size of a tumor is reduced by at least 5%. In furtheror additional embodiments, the size of a tumor is reduced by at least10%. In further or additional embodiments, the size of a tumor isreduced by at least 20%. In further or additional embodiments, the sizeof a tumor is reduced by at least 25%. In further or additionalembodiments, the size of a tumor is reduced by at least 30%. In furtheror additional embodiments, the size of a tumor is reduced by at least40%. In further or additional embodiments, the size of a tumor isreduced by at least 50%. In further or additional embodiments, the sizeof a tumor is reduced by at least 60%. In further or additionalembodiments, the size of a tumor is reduced by at least 70%. In furtheror additional embodiments, the size of a tumor is reduced by at least75%. In further or additional embodiments, the size of a tumor isreduced by at least 80%. In further or additional embodiments, the sizeof a tumor is reduced by at least 85%. In further or additionalembodiments, the size of a tumor is reduced by at least 90%. In furtheror additional embodiments, the size of a tumor is reduced by at least95%. In further or additional embodiments, the tumor is eradicated. Insome embodiments, the size of a tumor does not increase. In someembodiments, tumor proliferation is reduced. In some embodiments, tumorproliferation is reduced by at least 1%. In some embodiments, tumorproliferation is reduced by at least 2%. In some embodiments, tumorproliferation is reduced by at least 3%. In some embodiments, tumorproliferation is reduced by at least 4%. In some embodiments, tumorproliferation is reduced by at least 5%. In some embodiments, tumorproliferation is reduced by at least 10%. In some embodiments, tumorproliferation is reduced by at least 20%. In some embodiments, tumorproliferation is reduced by at least 25%. In some embodiments, tumorproliferation is reduced by at least 30%. In some embodiments, tumorproliferation is reduced by at least 40%. In some embodiments, tumorproliferation is reduced by at least 50%. In some embodiments, tumorproliferation is reduced by at least 60%. In some embodiments, tumorproliferation is reduced by at least 70%. In some embodiments, tumorproliferation is reduced by at least 75%. In some embodiments, tumorproliferation is reduced by at least 80%. In some embodiments, tumorproliferation is reduced by at least 90%. In some embodiments, tumorproliferation is reduced by at least 95%. In some embodiments, tumorproliferation is prevented. In some embodiments, the compositioncomprising a compound of formula I is administered in combination withan additional therapy. In further or additional embodiments, theadditional therapy is radiation therapy, chemotherapy or a combinationof both. In further or additional embodiments, the compositioncomprising a compound of formula I is administered in combination withat least one therapeutic agent. In further or additional embodiments,the therapeutic agent is selected from the group of cytotoxic agents,anti-angiogenesis agents and anti-neoplastic agents. In further oradditional embodiments, the anti-neoplastic agent is selected from thegroup of consisting of alkylating agents, anti-metabolites,epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors,procarbazines, mitoxantrones, platinum coordination complexes,biological response modifiers and growth inhibitors,hormonal/anti-hormonal therapeutic agents, and haematopoietic growthfactors. In further or additional embodiments, the therapeutic agent isselected from taxol, bortezomib or both. In some embodiments, thecomposition is administered orally, intraduodenally, parenterally(including intravenous, subcutaneous, intramuscular, intravascular or byinfusion), topically or rectally. In further or additional embodimentsthe amount of compound of formula I is in the range of about 0.001 toabout 1000 mg/kg body weight/day. In further or additional embodimentsthe amount of compound of formula I is in the range of about 0.5 toabout 50 mg/kg body weight/day. In further or additional embodiments theamount of compound of formula I is about 0.001 to about 7 g/day. Infurther or additional embodiments the amount of compound of formula I isabout 0.01 to about 7 g/day. In further or additional embodiments theamount of compound of formula I is about 0.02 to about 5 g/day. Infurther or additional embodiments the amount of compound of formula I isabout 0.05 to about 2.5 g/day. In further or additional embodiments theamount of compound of formula I is about 0.1 to about 1 g/day. Infurther or additional embodiments, dosage levels below the lower limitof the aforesaid range may be more than adequate. In further oradditional embodiments, dosage levels above the upper limit of theaforesaid range may be required. In further or additional embodimentsthe compound of formula I is administered in a single dose, once daily.In further or additional embodiments the compound of formula I isadministered in multiple doses, more than once per day. In further oradditional embodiments the compound of formula I is administered twicedaily. In further or additional embodiments the compound of formula I isadministered three times per day. In further or additional embodimentsthe compound of formula I is administered four times per day. In furtheror additional embodiments the compound of formula I is administered morethan four times per day. In some embodiments, the individual sufferingfrom cancer is a mammal. In further or additional embodiments, theindividual is a human. In further or additional embodiments, aneffective amount of a composition comprising a pharmaceuticallyacceptable salt of a compound of formula I is administered.

In other aspects, the present invention is directed to a method forachieving an effect in a patient comprising the administration of aneffective amount of a composition comprising a compound of formula I ora pharmaceutically acceptable salt, solvate, polymorph, ester, tautomeror prodrug thereof, to a patient, wherein the effect is selected fromthe group consisting of inhibition of various cancers, immunologicaldiseases, and inflammatory diseases. In some embodiments, the effect isinhibition of various cancers. In further or additional embodiments, theeffect is inhibition of immunological diseases. In further or additionalembodiments, the effect is inhibition inflammatory diseases.

In other aspects, the present invention is directed to use of a compoundof formula I or a pharmaceutically acceptable salt, solvate, polymorph,ester, tautomer or prodrug thereof in the preparation of apharmaceutical composition for the inhibiting various cancers,immunological diseases, and/or inflammatory diseases.

In some embodiments, the composition comprising a compound of formula Iis administered in combination with an additional therapy. In further oradditional embodiments, the additional therapy is radiation therapy,chemotherapy or a combination of both. In further or additionalembodiments, the composition comprising a compound of formula I isadministered in combination with at least one therapeutic agent. In someembodiments, the composition is administered orally, intraduodenally,parenterally (including intravenous, subcutaneous, intramuscular,intravascular or by infusion), topically or rectally. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.001 to about 1000 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is in therange of about 0.5 to about 50 mg/kg body weight/day. In further oradditional embodiments the amount of compound of formula I is about0.001 to about 7 g/day. In further or additional embodiments the amountof compound of formula I is about 0.01 to about 7 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.02to about 5 g/day. In further or additional embodiments the amount ofcompound of formula I is about 0.05 to about 2.5 g/day. In further oradditional embodiments the amount of compound of formula I is about 0.1to about 1 g/day. In further or additional embodiments, dosage levelsbelow the lower limit of the aforesaid range may be more than adequate.In further or additional embodiments, dosage levels above the upperlimit of the aforesaid range may be required. In further or additionalembodiments the compound of formula I is administered in a single dose,once daily. In further or additional embodiments the compound of formulaI is administered in multiple doses, more than once per day. In furtheror additional embodiments the compound of formula I is administeredtwice daily. In further or additional embodiments the compound offormula I is administered three times per day. In further or additionalembodiments the compound of formula I is administered four times perday. In further or additional embodiments the compound of formula I isadministered more than four times per day. In some embodiments, theindividual suffering from cancer is a mammal. In further or additionalembodiments, the individual is a human. In further or additionalembodiments, an effective amount of a composition comprising apharmaceutically acceptable salt of a compound of formula I isadministered.

In other aspects, the present invention is directed to a process forpreparing a compound of formula I or a pharmaceutically acceptable salt,solvate, polymorph, ester, tautomer or prodrug thereof.

DETAILED DESCRIPTION

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized.

While preferred embodiments of the present invention have been shown anddescribed herein such embodiments are provided by way of example only.It should be understood that various alternatives to the embodiments ofthe invention described herein may be employed in practicing theinvention. Those ordinary skilled in the art will appreciate thatnumerous variations, changes, and substitutions are possible withoutdeparting from the invention. It is intended that the following claimsdefine the scope of aspects of the invention and that methods andstructures within the scope of these claims and their equivalents becovered thereby.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, without limitation, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Certain Chemical Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. All patents, patentapplications, published materials referred to throughout the entiredisclosure herein, unless noted otherwise, are incorporated by referencein their entirety. In the event that there is a plurality of definitionsfor terms herein, those in this section prevail. Where reference is madeto a URL or other such identifier or address, it is understood that suchidentifiers can change and particular information on the internet cancome and go, but equivalent information can be found by searching theinternet or other appropriate reference source. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. It should alsobe noted that use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes”, and “included” is not limiting. Likewise, use ofthe term “comprising” as well as other forms, such as “comprise”,“comprises”, and “comprised” is not limiting.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, IR andUV/Vis spectroscopy and pharmacology, within the skill of the art areemployed. Unless specific definitions are provided, the nomenclatureemployed in connection with, and the laboratory procedures andtechniques of analytical chemistry, synthetic organic chemistry, andmedicinal and pharmaceutical chemistry described herein are those knownin the art. Standard techniques can be used for chemical syntheses,chemical analyses, pharmaceutical preparation, formulation, anddelivery, and treatment of patients. Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods well known in the art and as describedin various general and more specific references that are cited anddiscussed throughout the present specification. Throughout thespecification, groups and substituents thereof can be chosen by oneskilled in the field to provide stable moieties and compounds.

Where substituent groups are specified by their conventional chemicalformulas, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left. As a non-limiting example, CH₂O isequivalent to OCH₂.

Unless otherwise noted, the use of general chemical terms, such asthough not limited to “alkyl,” “amine,” “aryl,” are equivalent to theiroptionally substituted forms. For example, “alkyl,” as used herein,includes optionally substituted alkyl.

The terms “moiety”, “chemical moiety”, “group” and “chemical group”, asused herein refer to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “catalytic group” refers to a chemical functional group thatassists catalysis by acting to lower the activation barrier to reaction.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. For example, “optionally substitutedalkyl” means either “alkyl” or “substituted alkyl” as defined below.Further, an optionally substituted group may be un-substituted (e.g.,CH₂CH₃), fully substituted (e.g., CF₂CF₃), mono-substituted (e.g.,CH₂CH₂F) or substituted at a level anywhere in-between fully substitutedand mono-substituted (e.g., CH₂CHF₂, CF₂CH₃, CFHCHF₂, etc). It will beunderstood by those skilled in the art with respect to any groupcontaining one or more substituents that such groups are not intended tointroduce any substitution or substitution patterns (e.g., substitutedalkyl includes optionally substituted cycloalkyl groups, which in turnare defined as including optionally substituted alkyl groups,potentially ad infinitum) that are sterically impractical and/orsynthetically non-feasible. Thus, any substituents described shouldgenerally be understood as having a maximum molecular weight of about1,000 daltons, and more typically, up to about 500 daltons (except inthose instances where macromolecular substituents are clearly intended,e.g., polypeptides, polysaccharides, polyethylene glycols, DNA, RNA andthe like).

As used herein, C₁-Cn, includes C₁-C₂, C₁-C₃ . . . C₁-Cn. By way ofexample only, a group designated as “C₁-C₄” indicates that there are oneto four carbon atoms in the moiety, i.e. groups containing 1 carbonatom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as theranges C₁-C₂ and C₁-C₃. Thus, by way of example only, “C₁-C₄ alkyl”indicates that there are one to four carbon atoms in the alkyl group,i.e., the alkyl group is selected from among methyl, ethyl, propyl,iso-propyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Whenever itappears herein, a numerical range such as “1 to 10” refers to eachinteger in the given range; e.g., “1 to 10 carbon atoms” means that thegroup may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbonatoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9carbon atoms, or 10 carbon atoms.

The term “hydrocarbon” as used herein, alone or in combination, refersto a compound or chemical group containing only carbon and hydrogenatoms.

The terms “heteroatom” or “hetero” as used herein, alone or incombination, refer to an atom other than carbon and hydrogen.Heteroatoms are independently selected from among oxygen, nitrogen,sulfur, phosphorous, silicon, selenium and tin but are not limited tothese atoms. In embodiments in which two or more heteroatoms arepresent, the two or more heteroatoms can be the same as each another, orsome or all of the two or more heteroatoms can each be different fromthe others.

The term “alkyl” as used herein, alone or in combination, refers to anoptionally substituted straight-chain, or optionally substitutedbranched-chain saturated hydrocarbon monoradical having from one toabout ten carbon atoms, more preferably one to six carbon atoms.Examples include, but are not limited to methyl, ethyl, n-propyl,isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyland hexyl, and longer alkyl groups, such as heptyl, octyl and the like.Whenever it appears herein, a numerical range such as “C₁-C₆ alkyl” or“C₁₋₆ alkyl”, means that the alkyl group may consist of 1 carbon atom, 2carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbonatoms, although the present definition also covers the occurrence of theterm “alkyl” where no numerical range is designated.

The term “aliphatic” as used herein, alone or in combination, refers toan optionally substituted, straight-chain or branched-chain, non-cyclic,saturated, partially unsaturated, or fully unsaturated nonaromatichydrocarbon. Thus, the term collectively includes alkyl, alkenyl andalkynyl groups.

The term “carbon chain” as used herein, alone or in combination, refersto any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl orheteroalkynyl group, which is linear, cyclic, or any combinationthereof. If the chain is part of a linker and that linker comprises oneor more rings as part of the core backbone, for purposes of calculatingchain length, the “chain” only includes those carbon atoms that composethe bottom or top of a given ring and not both, and where the top andbottom of the ring(s) are not equivalent in length, the shorter distanceshall be used in determining the chain length. If the chain containsheteroatoms as part of the backbone, those atoms are not calculated aspart of the carbon chain length.

The terms “cycle”, “cyclic”, “ring” and “membered ring” as used herein,alone or in combination, refer to any covalently closed structure,including alicyclic, heterocyclic, aromatic, heteroaromatic andpolycyclic fused or non-fused ring systems as described herein. Ringscan be optionally substituted. Rings can form part of a fused ringsystem. The term “membered” is meant to denote the number of skeletalatoms that constitute the ring. Thus, by way of example only,cyclohexane, pyridine, pyran and pyrimidine are six-membered rings andcyclopentane, pyrrole, tetrahydrofuran and thiophene are five-memberedrings.

The term “cycloalkyl” as used herein, alone or in combination, refers toan optionally substituted, saturated, hydrocarbon monoradical ring,containing from three to about fifteen ring carbon atoms or from threeto about ten ring carbon atoms, though may include additional, non-ringcarbon atoms as substituents (e.g. methylcyclopropyl).

A non-limiting example of “cycloalkyl” includes azinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl,3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl,3H-indolyl and quinolizinyl and the like. The terms also include allring forms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides.

The term “aromatic” as used herein, refers to a planar, cyclic orpolycyclic, ring moiety having a delocalized at-electron systemcontaining 4n+2 n electrons, where n is an integer. Aromatic rings canbe formed by five, six, seven, eight, nine, or more than nine atoms.Aromatics can be optionally substituted and can be monocyclic orfused-ring polycyclic. The term aromatic encompasses both all carboncontaining rings (e.g., phenyl) and those rings containing one or moreheteroatoms (e.g., pyridine).

The term “aryl” as used herein, alone or in combination, refers to anoptionally substituted aromatic hydrocarbon radical of six to abouttwenty ring carbon atoms, and includes fused and non-fused aryl rings. Afused aryl ring radical contains from two to four fused rings where thering of attachment is an aryl ring, and the other individual rings maybe alicyclic, heterocyclic, aromatic, heteroaromatic or any combinationthereof. Further, the term aryl includes fused and non-fused ringscontaining from six to about twelve ring carbon atoms, as well as thosecontaining from six to about ten ring carbon atoms. A non-limitingexample of a single ring aryl group includes phenyl; a fused ring arylgroup includes naphthyl, phenanthrenyl, anthracenyl, azulenyl; and anon-fused bi-aryl group includes biphenyl. The term “heteroaryl” as usedherein, alone or in combination, refers to optionally substitutedaromatic mono-radicals containing from about five to about twentyskeletal ring atoms, where one or more of the ring atoms is a heteroatomindependently selected from among oxygen, nitrogen, sulfur, phosphorous,silicon, selenium and tin but not limited to these atoms and with theproviso that the ring of said group does not contain two adjacent O or Satoms. In embodiments in which two or more heteroatoms are present inthe ring, the two or more heteroatoms can be the same as each another,or some or all of the two or more heteroatoms can each be different fromthe others. The term heteroaryl includes optionally substituted fusedand non-fused heteroaryl radicals having at least one heteroatom. Theterm heteroaryl also includes fused and non-fused heteroaryls havingfrom five to about twelve skeletal ring atoms, as well as those havingfrom five to about ten skeletal ring atoms. Bonding to a heteroarylgroup can be via a carbon atom or a heteroatom. Thus, as a non-limitingexample, an imidiazole group may be attached to a parent molecule viaany of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl),or its nitrogen atoms (imidazol-1-yl or imidazol-3-yl). Likewise, aheteroaryl group may be further substituted via any or all of its carbonatoms, and/or any or all of its heteroatoms. A fused heteroaryl radicalmay contain from two to four fused rings where the ring of attachment isa heteroaromatic ring and the other individual rings may be alicyclic,heterocyclic, aromatic, heteroaromatic or any combination thereof. Anon-limiting example of a single ring heteroaryl group includes pyridyl;fused ring heteroaryl groups include benzimidazolyl, quinolinyl,acridinyl; and a non-fused bi-heteroaryl group includes bipyridinyl.Further examples of heteroaryls include, without limitation, furanyl,thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl,benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl,benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl,isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl,indazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, pyrrolyl,pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl,quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyland the like, and their oxides, such as for example pyridyl-N-oxide andthe like.

The term “heterocycle” as used herein, alone or in combination, referscollectively to heteroalicyclyl and heteroaryl groups. Herein, wheneverthe number of carbon atoms in a heterocycle is indicated (e.g., C₁-C₆heterocycle), at least one non-carbon atom (the heteroatom) must bepresent in the ring. Designations such as “C₁-C₆ heterocycle” refer onlyto the number of carbon atoms in the ring and do not refer to the totalnumber of atoms in the ring. Designations such as “4-6 memberedheterocycle” refer to the total number of atoms that are contained inthe ring (i.e., a four, five, or six membered ring, in which at leastone atom is a carbon atom, at least one atom is a heteroatom and theremaining two to four atoms are either carbon atoms or heteroatoms). Forheterocycles having two or more heteroatoms, those two or moreheteroatoms can be the same or different from one another. Heterocyclescan be optionally substituted. Non-aromatic heterocyclic groups includegroups having only three atoms in the ring, while aromatic heterocyclicgroups must have at least five atoms in the ring. Bonding (i.e.attachment to a parent molecule or further substitution) to aheterocycle can be via a heteroatom or a carbon atom.

The terms “halogen”, “halo” or “halide” as used herein, alone or incombination refer to fluoro, chloro, bromo and iodo.

The term “alkoxy” as used herein, alone or in combination, refers to analkyl ether radical, O-alkyl, including the groups O-aliphatic andO-carbocycle, wherein the alkyl, aliphatic and carbocycle groups may beoptionally substituted, and wherein the terms alkyl, aliphatic andcarbocycle are as defined herein. Non-limiting examples of alkoxyradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tertbutoxy and the like.

The term “sulfonyl” as used herein, alone or in combination, refers tothe diradical —S(—O)₂.

The terms “sulfonamide”, “sulfonamido” and “sulfonamidyl” as usedherein, alone or in combination, refer to the diradical groups—S(—O)₂—NH— and —NH—S(═O)₂.

The terms “sulfamide”, “sulfamido” and “sulfamidyl” as used herein,alone or in combination, refer to the diradical group NHS(—O)₂NH.

Certain Pharmaceutical Terminology

The term “PI3K inhibitor” as used herein refers to a compound thatexhibits an IC₅₀, with respect to PI3K activity, of no more than about100 μM or not more than about 50 μM, as measured in the PI3 kinase assaydescribed generally herein. “IC₅₀” is that concentration of inhibitorwhich reduces the activity of an enzyme (e.g., PI3K) to half-maximallevel. Compounds described herein have been discovered to exhibitinhibition against PI3K. Compounds of the present invention preferablyexhibit an IC₅₀ with respect to PI3K of no more than about 10 μM, morepreferably, no more than about 5 μM, even more preferably not more thanabout 1 μM, and most preferably, not more than about 200 nM, as measuredin the PI3 kinase assay described herein.

The term “subject”, “patient” or “individual” as used herein inreference to individuals suffering from a disorder, a disorder, acondition, and the like, encompasses mammals and non-mammals. Examplesof mammals include, but are not limited to, any member of the Mammalianclass: humans, non-human primates such as chimpanzees, and other apesand monkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. Examples of non-mammals include, but are not limited to, birds,fish and the like. In one embodiment of the methods and compositionsprovided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, abating or amelioratinga disease or condition symptoms, preventing additional symptoms,ameliorating or preventing the underlying metabolic causes of symptoms,inhibiting the disease or condition, e.g., arresting the development ofthe disease or condition, relieving the disease or condition, causingregression of the disease or condition, relieving a condition caused bythe disease or condition, or stopping the symptoms of the disease orcondition, and are intended to include prophylaxis. The terms furtherinclude achieving a therapeutic benefit and/or a prophylactic benefit.By therapeutic benefit is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forprophylactic benefit, the compositions may be administered to a patientat risk of developing a particular disease, or to a patient reportingone or more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

The terms “effective amount”, “therapeutically effective amount” or“pharmaceutically effective amount” as used herein, refer to asufficient amount of at least one agent or compound being administeredwhich will relieve to some extent one or more of the symptoms of thedisease or condition being treated. The result can be reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in a disease. An appropriate “effective” amount inany individual case may be determined using techniques, such as a doseescalation study.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein, e.g., as discussed in Goodman and Gilman, ThePharmacological Basis of Therapeutics, current ed.; Pergamon; andRemington's, Pharmaceutical Sciences (current edition), Mack PublishingCo., Easton, Pa. In preferred embodiments, the compounds andcompositions described herein are administered orally.

The term “acceptable” as used herein, with respect to a formulation,composition or ingredient, means having no persistent detrimental effecton the general health of the subject being treated.

The term “pharmaceutically acceptable” as used herein, refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compounds described herein, andis relatively nontoxic, i.e., the material may be administered to anindividual without causing undesirable biological effects or interactingin a deleterious manner with any of the components of the composition inwhich it is contained.

The term “pharmaceutical composition,” as used herein, refers to abiologically active compound, optionally mixed with at least onepharmaceutically acceptable chemical component, such as, though notlimited to carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients.

The term “carrier” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The term “agonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme activator or a hormone modulator whichenhances the activity of another molecule or the activity of a receptorsite.

The term “antagonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme inhibitor, or a hormone modulator, whichdiminishes, or prevents the action of another molecule or the activityof a receptor site.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule thatinteracts with a target either directly or indirectly. The interactionsinclude, but are not limited to, the interactions of an agonist and anantagonist.

The term “pharmaceutically acceptable salt” as used herein, refers tosalts that retain the biological effectiveness of the free acids andbases of the specified compound and that are not biologically orotherwise undesirable. Compounds described herein may possess acidic orbasic groups and therefore may react with any of a number of inorganicor organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. These salts can be prepared in situduring the final isolation and purification of the compounds of theinvention, or by separately reacting a purified compound in its freebase form with a suitable organic or inorganic acid, and isolating thesalt thus formed. Examples of pharmaceutically acceptable salts includethose salts prepared by reaction of the compounds described herein witha mineral or organic acid or an inorganic base, such salts including,acetate, acrylate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, bisulfite, bromide, butyrate,butyn-1,4-dioate, camphorate, camphorsulfonate, caprylate,chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate,digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate,hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate,malonate, methanesulfonate, mandelate. metaphosphate, methoxybenzoate,methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate,2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate,persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,propionate, pyrosulfate, pyrophosphate, propiolate, phthalate,phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate,sulfate, sulfite, suberate, sebacate, sulfonate, tartrate, thiocyanate,tosylate undeconate and xylenesulfonate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts (See examples at Berge et al., J. Pharm. Sci. 1977, 66,1-19.). Further, those compounds described herein which may comprise afree acid group may react with a suitable base, such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cation,with ammonia, or with a pharmaceutically acceptable organic primary,secondary or tertiary amine. Representative alkali or alkaline earthsalts include the lithium, sodium, potassium, calcium, magnesium, andaluminum salts and the like. Illustrative examples of bases includesodium hydroxide, potassium hydroxide, choline hydroxide, sodiumcarbonate, IV′ (C₁₋₄ alkyl)₄, and the like. Representative organicamines useful for the formation of base addition salts includeethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine,piperazine and the like. It should be understood that the compoundsdescribed herein also include the quaternization of any basicnitrogen-containing groups they may contain. Water or oil-soluble ordispersible products may be obtained by such quaternization. See, forexample, Berge et al., supra.

The term “solvate” as used herein refers to a combination of a compoundof this invention with a solvent molecule formed by solvation. In somesituations, the solvate refers to a hydrate, i.e., the solvent moleculeis a water molecule, the combination of a compound of this invention andwater forms a hydrate.

The term “polymorph” or “polymorphism” as used herein refers to acompound of this invention present in different crystal lattice forms.

The term “ester” as used herein refers to a derivative of a compound ofthis invention derived from an oxoacid group and a hydroxyl group,either one of which can be present at the compound of this invention.

The term “tautomer” as used herein refers to an isomer readilyinterconverted from a compound of this invention by e.g., migration of ahydrogen atom or proton.

The term “pharmaceutically acceptable derivative or prodrug” as usedherein, refers to any pharmaceutically acceptable salt, ester, salt ofan ester or other derivative of a compound of this invention, which,upon administration to a recipient, is capable of providing, eitherdirectly or indirectly, a compound of this invention or apharmaceutically active metabolite or residue thereof. Particularlyfavored derivatives or prodrugs are those that increase thebioavailability of the compounds of this invention when such compoundsare administered to a patient (e.g., by allowing orally administeredcompound to be more readily absorbed into blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system).

Pharmaceutically acceptable prodrugs of the compounds described hereininclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, amino acidconjugates, phosphate esters, metal salts and sulfonate esters. Variousforms of prodrugs are well known in the art. See for example Design ofProdrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology,Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard,H. “Design and Application of Prodrugs” in A Textbook of Drug Design andDevelopment, Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p.113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8,1-38, each of which is incorporated herein by reference. The prodrugsdescribed herein include, but are not limited to, the following groupsand combinations of these groups; amine derived prodrugs: Hydroxyprodrugs include, but are not limited to acyloxyalkyl esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters and disulfidecontaining esters.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration of a desired effect. Thus, inregard to enhancing the effect of therapeutic agents, the term“enhancing” refers to the ability to increase or prolong, either inpotency or duration, the effect of other therapeutic agents on a system.

An “enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “pharmaceutical combination”, “administering an additionaltherapy”, “administering an additional therapeutic agent” and the like,as used herein, refer to a pharmaceutical therapy resulting from mixingor combining more than one active ingredient and includes both fixed andnon-fixed combinations of the active ingredients. The term “fixedcombination” means that at least one of the compounds described herein,and at least one co-agent, are both administered to a patientsimultaneously in the form of a single entity or dosage. The term“non-fixed combination” means that at least one of the compoundsdescribed herein, and at least one co-agent, are administered to apatient as separate entities either simultaneously, concurrently orsequentially with variable intervening time limits, wherein suchadministration provides effective levels of the two or more compounds inthe body of the patient. These also apply to cocktail therapies, e.g.the administration of three or more active ingredients.

The terms “co-administration”, “administered in combination with” andtheir grammatical equivalents or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments the compoundsdescribed herein will be co-administered with other agents. These termsencompass administration of two or more agents to an animal so that bothagents and/or their metabolites are present in the animal at the sametime. They include simultaneous administration in separate compositions,administration at different times in separate compositions, and/oradministration in a composition in which both agents are present. Thus,in some embodiments, the compounds of the invention and the other agent(s) are administered in a single composition.

The term “metabolite,” as used herein, refers to a derivative of acompound which is formed when the compound is metabolized.

The term “active metabolite,” as used herein, refers to a biologicallyactive derivative of a compound that is formed when the compound ismetabolized.

The term “metabolized,” as used herein, refers to the sum of theprocesses (including, but not limited to, hydrolysis reactions andreactions catalyzed by enzymes) by which a particular substance ischanged by an organism. Thus, enzymes may produce specific structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulphydryl groups. Further informationon metabolism may be obtained from The Pharmacological Basis ofTherapeutics, 9th Edition, McGraw-Hill (1996).

SYNTHETIC PROCEDURES AND EXAMPLES

The preparation of compounds of formula I is outlined below:

Scheme 1 above illustrates the preparation of pyridopyrimidineintermediates (8). Cyanopyridine derivative (2) can be prepared viacyanation of dichloropyridine (1). Cyanopyridine (2) was treated withammonium hydroxide and sodium hydrosulfite to give aminopyridine (3).The pyridopyrimidone (4) was obtained by cyclization usingtriethoxymethane. Subsequent chlorination of pyrimidone (4) gavedichloropyridopyrimidine (5). The pyridopyrimidine (5) was substitutedby a compound (6) to provide compound (7), which was coupled withsynthesized Suzuki reagent to give the desired pyridopyrimidines (8).

Scheme 2 illustrates the preparation of arylsulfonamide derivatives(12). Aminopyridine or pyrimidine (11) was reacted witharylsulfonylchloride (10) to provide sulfonamide (11). The sulfonamide(11) was reacted with pinacol borane to give the desired borate (12)utilized in the Suzuki reaction described in Scheme 1.

Intermediate 16-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine

Step A: 6-chloro-3-nitropicolinonitrile

To a solution of 2,6-dichloro-3-nitropyridine (6.00 g, 31.1 mmol) in NMP(23.0 mL) was added copper(I) cyanide (3.06 g, 34.2 mmol) at roomtemperature. After stirred for 40 min at 180° C., the reaction mixturewas cooled to room temperature, and then poured into ice water. Afterstirring for 10 min, the mixture was extracted with EtOAc, washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography on SiO₂(Hex:EtOAc=10:1) to give 6-chloro-3-nitropicolinonitrile (2.54 g, 44%)as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.79 (1H, d, J=8.4Hz), 8.58 (1H, d, J=8.4 Hz).

Step B: 3-amino-6-chloropicolinamide

To a suspension of 6-chloro-3-nitropicolinonitrile (2.54 g, 13.8 mmol)in water (27.0 mL) was added NH₄OH (5.61 mL, 36.0 mmol) at roomtemperature. After stirring for 20 min at room temperature, Na₂S₂O₄(13.7 g, 79.0 mmol) was added to the mixture. After stirring for 3 hoursat room temperature, the reaction mixture was filtered, and washed withwater. The filtercake was dried under vacuum to give3-amino-6-chloropicolinamide (1.67 g, 70%) as a yellow solid. ¹H-NMR(CDCl₃, Varian 400 MHz) δ 5.36 (1H, brs), 6.00 (2H, brs), 7.00 (1H, d,J=8.8 Hz), 7.18 (1H, d, J=8.8 Hz), 7.63 (1H, brs).

Step C: 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one

A suspension of 3-amino-6-chloropicolinamide (1.67 g, 9.74 mmol) intriethyl orthoformate (73.0 mL) was refluxed for 3 hours. The reactionmixture was cooled to room temperature, and then filtered. Thefiltercake was dried under vacuum to give6-chloropyrido[3,2-d]pyrimidin-4(1H)-one (1.45 g, 82%) as a brown solid.¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.66 (1H, d, J=8.4 Hz), 8.00 (1H, s),8.03 (1H, d, J=1.2 Hz), 12.57 (1H, brs).

Step D: 4,6-dichloropyrido[3,2-d]pyrimidine

To a solution of 6-chloropyrido[3,2-d]pyrimidin-4(1H)-one (150 mg, 0.83mmol) in POCl₃ (2.0 mL) was added DIPEA (0.22 mL, 1.24 mmol) at roomtemperature. After stirring for 1 hour at 110° C., the reaction mixturewas cooled to room temperature. The reaction mixture was concentrated invacuo, and then diluted with water and extracted with dichlormethane.The combined organic layers were washed brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on SiO₂ (Hex:EtOAc=10:1) to give4,6-dichloropyrido[3,2-d]pyrimidine (120 mg, 73%) as a yellow solid.¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.87 (1H, d, J=8.8 Hz), 8.35 (1H, d,J=8.8 Hz), 9.14 (1H, s).

Step E: 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine

To a solution of tetrahydro-2H-pyran-4-ol (0.042 mL, 0.440 mmol) in DMF(1.60 mL) was added NaH (21.0 mg, 55% dispersion in mineral oil, 0.480mmol) at 0° C. After stirring for 30 min at room temperature,4,6-dichloropyrido[3,2-d]pyrimidine (80.0 mg, 0.400 mmol) was added tothe mixture at 0° C. After stirring for 2 hours at room temperature, thereaction mixture was quenched with saturated aq. NH₄Cl, and thenextracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography on SiO₂(Hex:EtOAc=3:1) to give6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (60.0mg, 57%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 2.02-2.11(2H, m), 2.18-2.23 (2H, m), 3.62-3.68 (2H, m), 4.08-4.13 (2H, m),5.59-5.63 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (2H, d, J=8.8 Hz), 8.81(1H, s).

Intermediate 2N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide

Step A: N-(5-bromopyridin-3-yl)benzenesulfonamide

To a solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) in pyridine(3.00 mL) was added benzenesulfonyl chloride (0.75 mL, 5.78 mmol)dropwise at 0° C. The mixture was stirred for 40 min at roomtemperature. The resulting solid was filtered, washed with water, anddried under vacuum to give N-(5-bromopyridin-3-yl)benzenesulfonamide(1.39 g, 77%) as a brown solid. ¹H-NMR (DMSO-d₆, Varian 400 MHz) δ7.58-7.68 (4H, m), 7.79-7.81 (2H, m), 8.27 (1H, d, J=2.4 Hz), 8.37 (1H,d, J=2.0 Hz), 10.91 (1H, brs).

Step B:N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene-sulfonamide

A mixture of N-(5-bromopyridin-3-yl)benzenesulfonamide (1.00 g, 3.19mmol), bis(pinacolato)diboron (0.89 g, 3.51 mmol), PdCl₂(dppf)₂CH₂Cl₂(0.13 g, 0.16 mmol) and potassium acetate (0.94 g, 9.58 mmol) in1,4-dioxane (7.51 mL) was stirred at 100° C. for 3 hours in a sealedtube. The reaction mixture was cooled to room temperature, filteredthrough a Celite pad and washed with EtOAc. The filtrate wasconcentrated in vacuo. The residue was triturated with dichloromethaneand the resulting solid was filtered. The filtercake was dried undervacuum to giveN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide(1.50 g, quent) as a brown solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.34(12H, s), 7.46 (2H, t, J=7.6 Hz), 7.57 (1H, t, J=7.6 Hz), 7.76 (2H, d,J=7.2 Hz), 7.84 (1H, d, J=1.2 Hz), 8.35 (1H, d, J=2.4 Hz), 8.71 (1H, d,J=1.2 Hz); NH peak was not detected.

Intermediate 3N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

Step A: 5-bromo-2-chloro-3-nitropyridine

To a solution of 5-bromo-3-nitropyridin-2(1H)-one (4.62 g, 21.10 mmol)in POCl₃ (46.2 ml) was added DMF (4.62 ml, 59.7 mmol) at roomtemperature. The mixture was refluxed for 2 hours, and then cooled toroom temperature and concentrated in vacuo. The residue was treated withsaturated aq. NaHCO₃ and extracted with EtOAc. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=3:1) to give 5-bromo-2-chloro-3-nitropyridine (4.24g, 85%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 8.37 (1H, d,J=2.4 Hz), 8.70 (1H, d, J=2.0 Hz).

Step B: 5-bromo-2-chloropyridin-3-amine

To a solution of 5-bromo-2-chloro-3-nitropyridine (4.24 g, 17.86 mmol)in EtOH (89 ml) was added Tin(II) chloride (16.9 g, 89.0 mmol) at roomtemperature. The mixture was refluxed for 1 hour, and then cooled toroom temperature, filtered through a Celite pad and washed with EtOAc.The filtrate was concentrated in vacuo. The residue was treated withsaturated aq. NaHCO₃, and extracted with EtOAc. The combined organiclayers were washed brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=3:1) to give 5-bromo-2-chloropyridin-3-amine (2.7 g,73%) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 5.89 (2H, brs),7.30 (1H, d, J=2.0 Hz), 7.66 (1H, d, J=2.4 Hz).

Step C: N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide

To a solution of 5-bromo-2-chloropyridin-3-amine (0.900 g, 4.34 mmol) inDCM (8.68 ml) was added pyridine (0.541 ml, 6.69 mmol) and2,4-difluorobenzene-1-sulfonyl chloride (0.851 ml, 6.33 mmol) at 0° C.After stiffing overnight at room temperature, the reaction mixture wasdiluted with DCM and treated with saturated aq. NaHCO₃. The resultingsolid was collected by filtration and washed with water to giveN-(5-bromo-2-chloropyridin-3-yl)-N-(2,4-difluorophenylsulfonyl)-2,4-difluorobenzenesulfonamide(0.65 g, 27%) as a white solid. The filtrate was extracted with DCM(2×50 mL), the combined organic layers were washed brine, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography on SiO₂ (Hex:EtOAc=5:1) to giveN-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.20 g,12%) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.26 (1H, t,J=8.4 Hz), 7.59 (1H, t, J=10.0 Hz), 7.81 (1H, dd, J=16.0, 7.6 Hz), 8.04(1H, d, J=2.4 Hz), 8.46 (1H, d, J=2.4 Hz), 11.1 (1H, brs).

Step D:N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture ofN-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide (1.12 g,2.92 mmol), potassium acetate (1.14 g, 11.6 mmol), BISPIN (0.890 g, 3.50mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (0.119 g, 0.146 mmol) in dioxane(6.87 ml) was refluxed for 3 hours. After cooling to room temperature,the reaction mixture was filtered through a Celite pad and washed withCH₂Cl₂ The filtrate was diluted with water and extracted with CH₂Cl₂(2×100 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography on SiO₂ (Hex:EtOAc=5:1) to giveN-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.835 g, 66%) as a brown oil. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.30(12H, s), 6.88-6.95 (2H, m), 7.79-7.85 (1H, m), 8.20 (1H, d, J=1.6 Hz),8.40 (1H, d, J=1.6 Hz), 7.63 (1H, brs); NH peak was not observed.

Intermediate 4N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

Step A: N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide

To a solution of 5-bromo-2-chloropyridin-3-amine (0.500 g, 2.89 mmol) inpyridine (1.45 ml) was dropwise added 2,4-difluorobenzene-1-sulfonylchloride (0.614 ml, 2.89 mmol) at 0° C. The mixture was stirred for 40min at room temperature and acidified with 1 N HCl. The residue wasextracted with EtOAc and the combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give N-(5-bromopyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.70 g,70% yield) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 6.92-7.04(2H, m), 7.76-7.84 (1H, m), 7.86-7.95 (1H, m), 8.27 (1H, d, J=2.4 Hz),8.44 (1H, d, J=2.4 Hz); NH peak was not observed.

Step B:N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture ofN-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.70 g,2.01 mmol), Potassium acetate (0.590 g, 6.01 mmol), BISPIN (0.611 g,2.41 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (0.164 g, 0.200 mmol) in dioxane(7.51 ml) was refluxed for 3 hours. After cooling to room temperature,the reaction mixture was filtered through a Celite pad and washed withCH₂Cl₂. The filtrate was diluted with water and extracted with CH₂Cl₂(2×100 mL). The combined organic layers were washed with brine, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography on SiO₂ (Hex:EtOAc=5:1) to giveN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.110 g, 14%) as a brown oil. ¹H-NMR (CDCl₃, Varian400 MHz) δ 1.33 (12H, s), 6.86-6.95 (2H, m), 7.82-7.98 (2H, m), 8.46(1H, d, J=2.8 Hz), 8.70 (1H, d, J=1.2 Hz); NH peak was not observed.

Intermediate 5N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide

Step A: N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide

To a solution of 5-bromo-2-chloropyridin-3-amine (1.00 g, 4.82 mmol) inpyridine (2.41 ml) was dropwise added benzenesulfonyl chloride (0.851 g,4.82 mmol) at 0° C. The mixture was stirred for 40 min at roomtemperature and acidified with 1 N HCl. The residue was extracted withEtOAc and the combined organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to giveN-(5-bromo-2-chloropyridin-3-yl)-N-(phenylsulfonyl)benzenesulfonamide(0.606 g, 26% yield) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ7.02 (1H, s), 7.47-7.56 (2H, m), 7.59-7.66 (1H, m), 7.78-7.86 (2H, m),8.16 (2H, dd, J=2.4, 7.2 Hz).

Step B:N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfon amide

A mixture of N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide (0.100g, 0.288 mmol), Potassium acetate (0.085 g, 0.863 mmol), BISPIN (0.080g, 0.316 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (0.023 g, 0.029 mmol) indioxane (0.8 ml) was subjected to microwave irradiation for 1 hour at110° C. After cooling to room temperature, the reaction mixture wasfiltered through a Celite pad and washed with CH₂Cl₂. The filtrate wasdiluted with water and extracted with CH₂Cl₂ (2×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to getN-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide(quant.) as a brown solid, which was used for the next step withoutfurther purification.

Intermediate 66-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine

To a solution of 1-methylpiperidin-4-ol (0.095 g, 0.825 mmol) in DMF(2.500 ml) was added NaH (0.041 g, 55% dispersion in mineral oil, 0.945mmol) at 0° C. After stirring for 30 min at room temperature, thereaction mixture was cooled to 0° C., followed by the addition of4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.15 g,0.750 mmol). After stiffing for 2 hours at room temperature, thereaction mixture was diluted with water, and extracted with EtOAc. Theorganic layers were dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=5:1) to give6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (0.09 g,43%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 2.03-2.12 (2H,m), 2.17-2.21 (2H, m), 2.22-2.32 (2H, m), 2.34 (3H, s), 2.84-2.89 (2H,m), 5.38-5.45 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz),8.81 (1H, s).

Intermediate 7 tert-butyl4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.201 g,1.000 mmol) in DMF (5.00 ml) was added NaH (0.052 g, 55% dispersion inmineral oil, 1.20 mmol) at 0° C. After stiffing for 30 min at roomtemperature, the reaction mixture was cooled to 0° C. and4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.2 g,1.000 mmol) was added to the mixture. After stiffing for 3 hours at roomtemperature, the reaction mixture was diluted with water, and extractedwith EtOAc. The organic layers were dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=5:1) to give tert-butyl4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate(0.236 g, 65%) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.49(9H, s), 1.91-1.99 (2H, m), 2.10-2.13 (2H, m), 3.21-3.27 (2H, m),3.83-3.97 (2H, m), 5.55-5.62 (1H, m), 7.74 (1H, d, J=8.8 Hz), 8.19 (1H,d, J=8.8 Hz), 8.41 (1H, s).

Intermediate 8 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine

To a solution of pyridin-3-ol (0.048 g, 0.500 mmol) in DMF (1.67 ml) wasadded NaH (0.027 g, 55% dispersion in mineral oil, 0.630 mmol) at 0° C.After stiffing for 30 min at room temperature, the reaction mixture wascooled to 0° C. and 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1,step D) (0.1 g, 0.500 mmol) was added to the mixture. After stiffing for2 hours at room temperature, the reaction mixture was diluted withwater, and extracted with EtOAc. The organic layers were dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on SiO₂ (Hex:EtOAc=5:1) to give6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090 g, 70%) as awhite solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.46 (1H, dd, J=8.0 and4.8 Hz), 7.66-7.69 (1H, m), 7.86 (1H, d, J=8.8 Hz), 8.31 (1H, d, J=8.8Hz), 8.61 (1H, d, J=4.4 Hz), 8.65 (1H, d, J=2.8 Hz), 8.80 (1H, s).

Intermediate 96-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-bis(boc-amino))pyrazine

Step A: 6-chloro-2-(N,N-bis(boc-amino)pyrazine

To a solution of 6-chloropyrazin-2-amine (0.3 g, 2.31 mmol) in THF (11.5ml) was added (Boc)₂O (1.34 ml, 5.79 mmol) and DMAP (0.141 g, 1.16 mmol)at room temperature. After stiffing for 2 hours at room temperature, thereaction mixture was concentrated in vacuo. The residue was purified bycolumn chromatography on SiO₂ (Hex:EtOAc=4:1) to give6-chloro-2-(N,N-bis(boc-amino)pyrazine (0.747 g, 98%) as a white solid.¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.47 (18H, s), 8.48 (1H, d, J=0.8 Hz),8.53 (1H, d, J=0.8 Hz).

Step B:6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-Bis(Boc-amino))-pyrazine

A mixture of 6-chloro-2-(N,N-bis(boc-amino)pyrazine (0.10 g, 0.303mmol), bis(pinacolato) diboron (0.085 g, 0.334 mmol), potassium acetate(0.089 g, 0.910 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (0.012 g, 0.015 mmol)in dioxane (1.52 ml) was subjected to microwave irradiation for 1 hourat 110° C., and cooled to room temperature. The reaction mixture wasfiltered through a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo to give6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-Bis(Boc-amino))pyrazine(0.128 g, quant) as a brown oil, which was used for the next stepwithout further purification. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.39(12H, s), 1.42 (12H, s), 8.52 (1H, s), 8.86 (1H, s).

Intermediate 106-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-Bis(Boc-amino))-pyrazine

A mixture of6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-2-(N,N-bis(boc-amino))pyrazine(0.872 g, 2.070 mmol) (Intermediate 9),6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (0.5 g,1.882 mmol) (Intermediate 1), PdCl₂(dppf)-CH₂Cl₂Adduct (0.154 g, 0.188mmol) and 1N aq. sodium bicarbonate (3.76 ml, 3.76 mmol) in dioxane(9.41 ml) was refluxed for 1 hour. The reaction mixture was cooled toroom temperature, and the reaction mixture was filtered through a pad ofCelite and washed with CH₂Cl₂. The filtrate was diluted with water andextracted with CH₂Cl₂ (2×100 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=1:1) to give6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-bis(boc-amino))pyrazine(0.845 g, 86%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.27(18H, s), 2.05-2.13 (2H, m), 2.17-2.19 (2H, m), 3.71-3.77 (2H, m),4.12-4.17 (2H, m), 5.67-5.71 (1H, m), 8.39 (1H, d, J=8.8 Hz), 8.69 (1H,s), 8.78 (1H, d, J=8.8 Hz), 8.85 (1H, s), 9.77 (1H, s).

Intermediate 114-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide

Step A: 4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide

To a solution of 5-bromopyridin-3-amine (0.300 g, 1.73 mmol) in pyridine(8.67 ml) was slowly added 4-bromo-2-chlorobenzene-1-sulfonyl chloride(0.600 g, 2.08 mmol) at 0° C. The reaction mixture was stirred for 2hours at room temperature. The reaction mixture was quenched with 1 Naq. HCl, and then extracted with DCM (2×50 mL). The combined organiclayers were washed brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The resulting residue was recrystallized fromEtOAc-hexanes to give4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide (0.530 g,72%) as a red solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.53-7.55 (1H, m),7.71 (1H, d, J=1.6 Hz), 7.78 (1H, t, J=2.2 Hz), 7.89 (1H, d, J=8.4 Hz),8.26 (1H, d, J=2.0 Hz). 8.44 (1H, d, J=2.4 Hz).

Step B:4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide

A mixture of 4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide(0.330 g, 0.774 mmol), bis(pinacolato)diboron (0.216 g, 0.851 mmol),potassium acetate (0.228 g, 2.32 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.0320 g,0.039 mmol) in dioxane (3.87 ml) was refluxed for 4 hours, and cooled toroom temperature. The reaction mixture was filtered through a Celite padand washed with DCM. The combined organic layers were washed brine,dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on SiO₂ (Hex:EtOAc=10:1)to give4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide(0.145 g, 40%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz): δ 1.34(12H, s), 7.35 (1H, s), 7.76-7.78 (2H, m), 7.92 (1H, s), 8.00 (1H, d,J=8.0 Hz), 8.24 (1H, d, J=2.4 Hz), 8.40 (1H, d, J=2.0 Hz).

Intermediate 125-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine

Step A: 5-bromo-3-(N,N-bis(boc-amino)pyridine

To a solution of 5-bromopyridin-3-amine (2.00 g, 11.6 mmol) in THF (57.8ml) were added (Boc)₂O (6.44 ml, 27.7 mmol) and DMAP (0.706 g, 5.78mmol) at room temperature. After stirred for 2 hours at roomtemperature, the reaction mixture was concentrated in vacuo. The residuewas purified by column chromatography on SiO₂ (Hex:EtOAc=30:1) to give5-bromo-3-(N,N-bis(boc-amino)pyridine (3.00 g, 70%) as a yellow solid.¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.44 (18H, s), 7.68 (1H, t, J=2.2 Hz),8.36 (1H, d, J=2.4 Hz), 8.60 (1H, d, J=2.0 Hz)

Step B:5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(N,N-bis(boc-amino)pyridine

A mixture of 5-bromo-3-(N,N-bis(boc-amino)pyridine (0.100 g, 0.268mmol), BISPIN (0.075 g, 0.295 mmol), potassium acetate (0.079 g, 0.804mmol) and PdCl₂(dppf)-CH₂Cl₂ (10.9 mg, 0.013 mmol) in dioxane (1.340 ml)was subjected to microwave irradiation for 1 hour at 110° C., and cooledto room temperature. The reaction mixture was filtered through a Celitepad and washed with DCM. The filtrate was concentrated in vacuo to give5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(N,N-bis(boc-amino)pyridine(0.113 g, quant) as a yellow solid, which was used for the next stepwithout further purification. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.27 (9H,s), 1.36 (9H, s), 1.43 (12H, s), 7.85-7.86 (1H, m), 8.47 (1H, d, J=2.8Hz), 8.84 (1H, d, J=1.6 Hz).

Step C:5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-3-(N,N-bis(boc-amino)pyridine

A mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(N,N-bis(boc-amino)pyridine(0.1 g, 0.238 mmol), BISPIN (0.070 g, 0.262 mmol), 1N aq. sodiumbicarbonate (0.476 ml, 0.476 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.019 g,0.024 mmol) in dioxane (1.20 ml) was subjected to microwave irradiationfor 1 hour at 110° C., and cooled to room temperature. The reactionmixture was filtered through a Celite pad and washed with DCM. Theresidue was purified by column chromatography on SiO₂ (Hex:EtOAc=1:1) togive5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-3-(N,N-bis(boc-amino)pyridine(0.09 g, 89%) as a brown solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.55(9H, s), 2.03-2.11 (2H, m), 2.22-2.26 (2H, m), 3.64-3.79 (2H, m),4.10-4.16 (2H, m), 5.64-5.69 (1H, m), 7.16 (1H, s), 8.27 (1H, d, J=8.8Hz), 8.34 (1H, d, J=8.8 Hz), 8.65 (1H, s), 8.80-8.72 (2H, m), 9.09 (1H,s).

Step D:5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine

To a solution of5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-3-(N,N-bis(boc-amino)pyridine(0.500 g, 0.955 mmol) in DCM (4.77 ml) was slowly added TFA (2.207 ml,28.6 mmol) at 0° C. After stirred for 4 hours at room temperature, thereaction mixture was quenched with 1N aq. NaOH, extracted with DCM. Theorganic layers was dried over MgSO₄, filtered and concentrated in vacuoto give5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine(0.309 g, quant) as a yellow solid, which was used for the next stepwithout further purification. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 2.04-2.12(2H, m), 2.23-2.28 (2H, m), 3.67-3.74 (2H, m), 3.91 (2H, s), 4.10-4.15(2H, m), 5.63-5.70 (1H, m), 7.85-7.86 (1H, s), 8.21-8.24 (2H, m), 8.32(1H, d, J=8.8 Hz), 8.73 (1H, d, J=2.0 Hz), 8.81 (1H, s).

Intermediate 13N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide

Step A: N-(5-bromopyridin-3-yl)benzamide

To a solution of 5-bromopyridin-3-amine (0.3 g, 1.734 mmol) in THF (8.67ml) was added TEA (0.363 ml, 2.60 mmol), and then benzoyl chloride(0.292 g, 2.081 mmol) was added to the mixture at 0° C. After stirredfor 2 hours at room temperature, the reaction mixture was quenched withsaturated aq. NaHCO₃ (50 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layers were washed with water and brine, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography on SiO₂ (Hex:EtOAc=10:1) to giveN-(5-bromopyridin-3-yl)benzamide (0.435 g, 91%) as a yellow solid.¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.48 (2H, t, J=7.6 Hz), 7.58 (1H, t,J=7.4 Hz), 7.85-7.88 (2H, m), 8.38 (1H, brs), 8.40 (1H, d, J=1.6 Hz),8.56-8.58 (2H, m).

Step B:N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide

A mixture of N-(5-bromopyridin-3-yl)benzamide (0.435 g, 1.57 mmol),BISPIN (0.438 g, 1.73 mmol), potassium acetate (0.462 g, 4.71 mmol) andPdCl₂(dppf)-CH₂Cl₂ (0.064 g, 0.078 mmol) in dioxane (7.85 ml) wasrefluxed for 2 hours, and cooled to room temperature. The reactionmixture was filtered through a Celite pad and washed with DCM. Thecombined organic layers were washed brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography on SiO₂ (Hex:EtOAc=1:1) to giveN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide(0.247 g, 49%) as a yellow oil. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.36(12H, s), 7.38-7.58 (4H, m), 7.90 (2H, d, J=7.2 Hz), 8.45 (1H, s), 8.72(1H, s), 8.95 (1H, s).

Intermediate 14N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzamide

Step A: 2,4-difluorobenzoyl chloride

To a solution of 2,4-difluorobenzoic acid (0.100 g, 0.633 mmol) in DCM(3.16 ml) were added oxalyl chloride (0.066 ml, 0.759 mmol) and DMF(0.490 μl, 6.33 μmol) at 0° C. The reaction mixture was stirred forovernight at room temperature. The reaction mixture was concentrated invacuo, which was used for the next step without further purification.¹H-NMR (CDCl₃, Varian 400 MHz) δ 6.92-9.98 (1H, m), 7.01-7.06 (1H, m),8.16-8.22 (1H, m).

Step B: N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzamide

To a solution of 2,4-difluorobenzoyl chloride (0.33 g, 1.591 mmol) inCHCl₃ (15.9 ml) were slowly added TEA (0.443 ml, 3.18 mmol) and5-bromo-2-chloropyridin-3-amine (0.337 g, 1.91 mmol) at 0° C. Thereaction mixture was stirred for 5 hours at room temperature. Thereaction mixture was quenched with saturated aq. NaHCO₃, and extractedwith DCM (2×50 mL). The combined organic layers were washed brine, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography on SiO₂ (Hex:EtOAc=30:1) to giveN-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzamide (0.185 g, 34%) asa white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 6.93-7.26 (2H, m),8.21-8.27 (2H, m), 9.08-9.12 (1H, m), 9.16-9.16 (1H, m).

Step C:N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzamide

A mixture of N-(5-bromo-2-chloropyridin-3-yl)-2,4-difluorobenzamide(0.127 g, 0.365 mmol), BISPIN (0.102 g, 0.402 mmol), potassium acetate(0.108 g, 1.10 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.015 g, 0.018 mmol) indioxane (1.83 ml) was refluxed for 2 hours, and cooled to roomtemperature. The reaction mixture was filtered through a Celite pad andwashed with DCM. The combined organic layers were washed brine, driedover anhydrous MgSO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography on SiO₂ (only EtOAc) to giveN-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzamide(0.127 g, 88%) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.36(12H, s), 6.96-7.02 (1H, m), 7.07-7.12 (1H, m), 8.22-8.28 (1H, m), 8.48(1H, s), 9.03-9.07 (1H, m), 9.17 (1H, s).

Intermediate 15 6-chloro-4-(cyclohexylthio)pyrido[3,2-d]pyrimidine

To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1,step D) (0.1 g, 0.500 mmol) in ACN (2.500 ml) were addedcyclohexanethiol (0.058 g, 0.500 mmol) and K₂CO₃ (0.069 g, 0.500 mmol)at room temperature. After stiffing overnight at room temperature, thereaction mixture was diluted with water and extracted with EtOAc (2×50mL). The combined organic layers were washed with 1N aq. NaOH and thenwashed with 1N aq. HCl. The organic layers were dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on SiO₂ (Hex:EtOAc=5:1) to give 6-chloro-4-(cyclohexylthio)pyrido[3,2-d]pyrimidine (0.129 g, 92%) as a yellow solid.¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.36-1.42 (1H, m), 1.48-1.69 (5H, m),1.80-1.86 (2H, m), 2.14-2.20 (2H, m), 4.10-4.16 (1H, m), 7.73 (1H, d,J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.98 (1H, s).

Intermediate 16 6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine

To a solution of cyclopentanol (0.050 ml, 0.550 mmol) in DMF (2.500 ml)was added NaH (0.026 g, 55% dispersion in mineral oil, 0.600 mmol) at 0°C. The reaction mixture was stirred for 30 min at room temperature,4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g,0.500 mmol) was added to the mixture at 0° C. After being stirred for 2hours at room temperature, the reaction mixture was diluted with water,and extracted with EtOAc. The organic layers were dried over MgSO₄filtered and concentrated in vacuo. The residue was purified by columnchromatography on SiO₂ (Hex:EtOAc=5:1) to give6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine (0.04 g, 32%) as ayellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz): δ 1.63-1.74 (2H, m),1.86-1.96 (2H, m), 1.99-2.07 (2H, m), 2.12-2.20 (2H, m), 5.72-5.77 (1H,m), 7.72 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.83 (1H, s).

Intermediate 176-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.05 g, 0.250 mmol), tetrahydro-2H-pyran-4-amine (0.029 ml, 0.275mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (2.041 mg, 2.500 μmol) and sodiumtert-butoxide (0.048 g, 0.500 mmol) in dioxane (1.250 ml) was refluxedfor 3 hours. After cooling to room temperature, the reaction mixture wasfiltered through a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=2:1) to give6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine(0.027 g, 41%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ1.68-1.78 (2H, m), 2.03-2.13 (2H, m), 3.58-3.67 (2H, m), 4.05-4.09 (2H,m), 4.36-4.46 (1H, m), 6.90 (1H, brs), 7.63 (1H, d, J=8.8 Hz), 8.05 (1H,d, J=8.8 Hz), 8.62 (1H, s).

Intermediate 18 6-chloro-N-cyclopentylpyrido[3,2-d]pyrimidin-4-amine

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.100 g, 0.500 mmol), cyclopentanamine (0.054 ml, 0.550 mmol),PdCl₂(dppf)-CH₂Cl₂Adduct (4.08 mg, 5.00 mmol) and sodium tert-butoxide(0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 3 hours.After cooling to room temperature, the reaction mixture was filteredthrough a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=1:1) to give6-chloro-N-cyclopentylpyrido[3,2-d]pyrimidin-4-amine (0.043 g, 35%) as ayellow oil. ¹H-NMR (CDCl₃, Varian 400 MHz)): 6 1.60-1.83 (6H, m),2.15-2.21 (2H, m), 4.55-4.60 (1H, m), 6.96 (1H, d, J=6.4 Hz), 7.59-7.62(1H, m), 8.02-8.04 (1H, m), 8.63 (1H, s).

Intermediate 19 6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.100 g, 0.500 mmol), cyclobutanamine (0.047 ml, 0.550 mmol),PdCl₂(dppf)-CH₂Cl₂Adduct (4.08 mg, 5.00 mmol) and sodium tert-butoxide(0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours.After cooling to room temperature, the reaction mixture was filteredthrough a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=1:1) to give6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine (0.098 g, 84%) as ayellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.79-1.89 (2H, m),2.06-2.17 (2H, m), 2.48-2.56 (2H, m), 4.71-4.82 (1H, m), 7.11 (1H, brs),7.61 (1H, d, J=8.8 Hz), 8.03 (1H, d, J=8.8 Hz), 8.61 (1H, s).

Intermediate 20 6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.100 g, 0.500 mmol), cyclopropanamine (0.038 ml, 0.550 mmol),PdCl₂(dppf)-CH₂Cl₂Adduct (4.08 mg, 5.00 mmol) and sodium tert-butoxide(0.096 g, 1.00 mmol) in dioxane (2.50 ml) was refluxed for 4 hours.After cooling to room temperature, the reaction mixture was filteredthrough a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=1:1) to give6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine (0.060 g, 54%) as ayellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 0.76-0.79 (2H, m),0.99-1.03 (2H, m), 3.02-3.06 (1H, m), 7.12 (1H, brs), 7.61-7.63 (1H, m),8.04-8.07 (1H, m), 8.73 (1H, s).

Intermediate 21N-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.100 g, 0.500 mmol), 3,5-dimethylisoxazol-4-amine (0.140 g, 1.250mmol) and sodium acetate (0.123 g, 1.50 mmol) in 5 ml of solvent(THF:H₂O=1:1) was refluxed for 1 hour. The reaction mixture was dilutedwith EtOAc. The organics were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude was purified by columnchromatography on SiO₂ (Hex:EtOAc=1:1) to getN-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine(0.082 g, 59%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 2.24(3H, s), 2.40 (3H, s), 7.74 (1H, d, J=8.8 Hz), 7.93 (1H, brs), 8.16((1H, d, J=8.8 Hz), 8.69 (1H, s).

Intermediate 226-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.100 g, 0.500 mmol), 6-methoxypyridin-3-amine (0.155 g, 1.250 mmol)and sodium acetate (0.123 g, 1.50 mmol) in 5 ml of solvent (THF:H₂O=1:1)was refluxed for 1 hour. The reaction mixture was diluted with EtOAc.The organics were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The crude was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to get6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine (0.085g, 59%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 3.97 (3H,s), 6.85 (1H, d, J=8.8 Hz), 7.71 (1H, d, J=8.8 Hz), 8.14 (1H, d, J=8.8Hz), 8.20 (1H, dd, J=2.8, 8.8 Hz), 8.55 (1H, d, J=2.8 Hz), 8.67 (1H, brs), 8.73 (1H, s).

Intermediate 236-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.200 g, 1.00 mmol), 4-(trifluoromethoxy)aniline (0.177 g, 1.00mmol) and sodium acetate (0.246 g, 3.00 mmol) in 5 ml of solvent(THF:H₂O=1:1) was refluxed for 1 hour. The reaction mixture was dilutedwith EtOAc. The organics were washed with brine, dried over Na₂SO₄,filtered and concentrated. The crued was purified by columnchromatography on SiO₂ (Hex:EtOAc=1:1) to get6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine(0.32 g, 94%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 7.30(1H, d, J=8.4 Hz), 7.72 (1H, d, J=8.8 Hz), 7.98 (1H, d, J=9.2 Hz), 8.15(1H, dd, J=8.8 Hz), 8.80 (1H, s), 8.90 (1H, br s).

Intermediate 24 tert-butyl4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate

A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, stepD) (0.100 g, 0.500 mmol), tert-butyl 4-aminopiperidine-1-carboxylate(0.110 g, 0.550 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (4.08 mg, 5.00 μmol) andsodium tert-butoxide (0.096 g, 1.00 mmol) in dioxane (2.50 ml) wasrefluxed for 4 hours After cooling to room temperature, the reactionmixture was filtered through a Celite pad and washed with CH₂Cl₂. Thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography on SiO₂ (Hex:EtOAc=1:1) to give tert-butyl4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate(0.089 g, 49%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.49(9H, s), 1.52-1.75 (2H, m), 2.05-2.16 (2H, m), 2.92-3.10 (2H, m),4.08-4.25 (2H, m), 4.35-4.42 (1H, m), 6.87 (1H, d, J=8.4 Hz), 7.63 (1H,d, J=8.8 Hz), 8.06 (1H, d, J=8.8 Hz), 8.62 (1H, s).

Example 1N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

To a solution of6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 1) (60.0 mg, 0.226 mmol) in 1,4-dioxane (1.20 mL) wasaddedN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide(Intermediate 2) (122 mg, 0.339 mmol), PdCl₂(dppf)₂CH₂Cl₂ (18.0 mg,0.0230 mmol), and 1N aq. NaHCO₃ (0.452 mL, 0.452 mmol) at roomtemperature. The reaction mixture was subjected to microwave irradiationfor 30 min at 120° C., and cooled to room temperature. The reactionmixture was filtered through a Celite pad and washed with EtOAc. Thefiltrate was diluted with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography on SiO₂ (Hex:EtOAc=3:1) to giveN-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(20.0 mg, 19%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.02-2.11 (2H, m), 2.23-2.27 (2H, m), 3.68-3.74 (2H, m), 4.10-4.15 (2H,m), 5.64-5.69 (1H, m), 7.07 (1H, brs), 7.47-7.51 (2H, m), 7.56-7.60 (1H,m), 7.85-7.88 (2H, m), 8.21 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz),8.38 (1H, s), 8.43 (1H, t, J=2.2 Hz), 8.83 (1H, s), 9.16 (1H, s);m/z=464.2 [M+1]⁺.

Example 2N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture ofN-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.02 g, 0.075 mmol) (Intermediate 3),6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 1) (0.032 g, 0.075 mmol), sodium bicarbonate (0.151 ml,0.151 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (6.15 mg, 7.53 mop in dioxane(0.376 ml) was refluxed for 3 hours. The reaction mixture was cooled toroom temperature, filtered through a Celite pad and washed with CH₂Cl₂.The filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on SiO₂ (Hex:EtOAc=2:1) to giveN-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.02 g, 50%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.06-2.12 (2H, m), 2.23-2.30 (2H, m), 3.66-3.76 (2H, m), 4.02-4.17 (2H,m), 5.66-5.72 (1H, m), 6.73-7.01 (2H, m), 7.53 (1H, brs), 7.92-7.98 (1H,m), 8.20 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz), 8.80 (1H, d, J=2.4Hz), 8.84 (1H, s), 8.92 (1H, d, J=2.4 Hz). m/z=534.3 [M+1]⁺.

Example 3N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture ofN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.110 g, 0.278 mmol) (Intermediate 4),6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 1) (0.081 g, 0.305 mmol), 1 N aq. sodium bicarbonate(0.555 ml, 0.555 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (23.0 mg, 2.80 mmol)in dioxane (2.78 ml) was subjected to microwave irradiation for 1 hourat 110° C. The reaction mixture was cooled to room temperature, filteredthrough a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=2:1) to giveN-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.15 g, 18%) as a yellow solid. ¹H-NMR (DMSO-d₆, Varian 400 MHz) δ1.78-1.98 (2H, m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H,m), 5.58-5.72 (1H, m), 7.20-7.42 (1H, m), 7.48-7.62 (2H, m), 7.90-8.05(1H, m), 8.36-8.52 (2H, m), 8.58 (1H, d, J=8.2 Hz), 8.86 (1H, s), 9.13(1H, s), 11.29 (1H, br s). m/z=500.1 [M+1]⁺.

Example 4N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

A mixture ofN-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.114 g, 0.290 mmol) (Intermediate 5),6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 1) (0.070 g, 0.263 mmol), 1 N aq. sodium bicarbonate(0.527 ml, 0.527 mmol) and PdCl₂(dppf)-CH₂Cl₂Adduct (22.0 mg, 2.60 mopin dioxane (1.5 ml) was subjected to microwave irradiation for 1 hour at110° C. The reaction mixture was cooled to room temperature, filteredthrough a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=2:1) to giveN-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(0.030 g, 23%) as a yellow solid. ¹H-NMR (DMSO-d₆, Varian 400 MHz) δ1.75-1.98 (2H, m), 2.12-2.26 (2H, m), 3.55-3.72 (2H, m), 3.90-4.05 (2H,m), 5.58-5.72 (1H, m), 7.50-7.70 (3H, m), 7.85 (1H, d, J=7.6 Hz), 8.45(1H, d, J=8.4 Hz), 8.58-8.72 (2H, m), 8.87 (1H, s), 9.04 (1H, br s),10.55 (1H, s). m/z=498.09 [M+1]⁺.

Example 5N-(2-chloro-5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 6) (0.03 g, 0.108 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.046 g, 0.108 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (8.79mg, 10.76 mop and sodium bicarbonate (0.215 ml, 0.215 mmol) in dioxane(0.538 ml) was refluxed for 3 hours. After cooling to room temperature,the reaction mixture was filtered through a Celite pad and washed withCH₂Cl₂. The filtrate was concentrated in vacuo. The residue was purifiedby prep TLC (EtOAc:MeOH=10:1) to giveN-(2-chloro-5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzene-sulfonamide(0.02 g, 34%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.10-2.22 (2H, m), 2.37 (2H, s), 2.62 (3H, s), 2.88-2.95 (2H, m),3.13-3.17 (2H, m), 5.64 (1H, brs), 6.86-6.94 (2H, m), 7.86-7.92 (1H, m),8.21 (1H, d, J=9.2 Hz), 8.34 (1H, d, J=8.8 Hz), 8.79 (1H, d, J=2.0 Hz),8.82 (1H, s), 8.91 (1H, brs). m/z=547.4 [M+1]⁺.

Example 6N-(5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide

A mixture of6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 6) (0.074 g, 0.265 mmol),N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (Intermediate 2) (0.143 g, 0.398 mmol),PdCl₂(dppf)-CH₂Cl₂Adduct (43.4 mg, 53.0 mop and 1N aq. sodiumbicarbonate (0.531 ml, 0.531 mmol) in dioxane (1.06 ml) was refluxed for3 hours. After cooling to room temperature, the reaction mixture wasfiltered through a Celite pad and washed with CH₂Cl₂. The filtrate wasconcentrated in vacuo. The residue was purified by prep TLC (EtOAc only)to giveN-(5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(0.018 g, 14%) as a yellow solid. ¹H-NMR (DMSO-d₆, Varian 400 MHz) δ1.88-1.99 (2H, m), 2.12-2.21 (2H, m), 2.26 (3H, s), 2.28-2.36 (2H, m),2.77-2.85 (2H, m), 5.43 (1H, s), 6.54 (1H, brs), 7.47-7.60 (4H, m),7.83-7.89 (2H, m), 8.31-8.39 (2H, m), 8.49 (1H, d, J=8.8 Hz), 8.84 (1H,s), 8.91 (1H, s). m/z=477.2 [M+1]⁺.

Example 7 tert-butyl4-(6-(5-(phenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)-piperidine-1-carboxylate

A mixture of tert-butyl4-(6-chloropyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate (0.3g, 0.822 mmol),N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene-sulfonamide(Intermediate 2) (0.355 g, 0.987 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.067g, 0.082 mmol) and 1N aq. sodium bicarbonate (1.64 ml, 1.64 mmol) indioxane (4.11 ml) was subjected to microwave irradiation for 30 min at120° C., and cooled to room temperature. The reaction mixture wasfiltered through a Celite pad and washed with EtOAc. The filtrate wasdiluted water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=1:1) to give tert-butyl4-(6-(5-(phenylsulfonamido)-pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate(0.15 g, 32%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.49(9H, s), 1.95-2.05 (2H, m), 2.14-2.18 (2H, m), 3.36-3.43 (2H, m),3.89-3.95 (2H, m), 5.63-5.37 (1H, m), 7.46-7.52 (2H, m), 7.56-7.60 (1H,m), 7.85 (1H, d, J=7.2 Hz), 8.21 (1H, d, J=8.8 Hz), 8.34 (1H, s), 8.37(1H, d, J=2.4 Hz), 8.41 (1H, d, J=2.0 Hz), 8.83 (1H, s), 9.14 (1H, d,J=1.6 Hz).

Example 8N-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

To a solution of tert-butyl4-(6-(5-(phenylsulfonamido)-pyridine-3-yl)pyrido[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate(0.15 g, 0.267 mmol) in DCM (1.333 ml) was added TFA (0.205 ml, 2.67mmol) at room temperature. After stirring for 30 min at roomtemperature, the reaction mixture was evaporated in vacuo, to giveN-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(0.123 g, 100%) as a yellow oil, which was used in the next step withoutfurther purification. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.87-1.92 (2H,m), 2.15-2.22 (2H, m), 2.79-2.85 (2H, m), 3.20-3.24 (2H, m), 5.58-5.62(1H, m), 7.39-7.42 (3H, m), 7.92-7.94 (2H, m), 8.18-8.20 (2H, m), 8.28(1H, s), 8.59 (1H, d, J=1.6 Hz), 8.74 (1H, s).

Example 9N-(5-(4-(1-acetylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide

To a solution ofN-(5-(4-(piperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide(0.082 g, 0.177 mmol) in DCM (0.886 ml) was added TEA (0.062 ml, 0.443mmol) at room temperature. After stiffing for 2 hours at roomtemperature, AcCl (0.019 ml, 0.266 mmol) was added to the mixture at 0°C. After stiffing overnight at room temperature, the reaction mixturewas diluted with water and extracted with CH₂Cl₂. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by prep TLC(DCM:MeOH=20:1) to giveN-(5-(4-(1-acetylpiperidin-4-yloxy)-pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(0.007 g, 7%) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.05-2.18 (2H, m), 2.19 (3H, s), 3.53-3.59 (2H, m), 3.65-3.76 (2H, m),3.89-3.40 (2H, m), 5.74-8.79 (1H, m), 7.44-7.48 (2H, m), 7.53-7.57 (1H,m), 7.86-7.89 (2H, m), 8.23 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz),8.46 (1H, d, J=2.8 Hz), 8.53 (1H, d, J=2.4 Hz), 8.84 (1H, s), 9.12 (1H,d, J=1.6 Hz). m/z=505.1 [M+1]⁺.

Example 10N-(5-(4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

A mixture of 6-chloro-4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidine (0.090g, 0.348 mmol) (Intermediate 8),N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (0.150 g, 0.418 mmol) (Intermediate 2), PdCl₂(dppf)-CH₂Cl₂Adduct(0.057 g, 0.070 mmol) and 1N aq. sodium bicarbonate (0.70 ml, 0.70 mmol)in dioxane (1.74 ml) was subjected to microwave irradiation for 30 minat 120° C., and cooled to room temperature. The reaction mixture wasfiltered through a Celite pad and washed with EtOAc. The filtrate wasdiluted water and extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (EtOAc only) to giveN-(5-(4-(pyridin-3-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfon-amide(0.20 g, 13%) as a yellow solid. ¹H-NMR (DMSO-d₆, Varian 400 MHz) δ7.45-7.49 (2H, m), 7.51-7.56 (1H, m), 7.61 (1H, dd, J=8.4 and 4.8 Hz),7.84-7.87 (2H, m), 7.92-7.95 (1H, m), 8.38 (1H, d, J=2.8 Hz), 8.45 (1H,s), 8.49-8.51 (2H, m), 8.53 (1H, dd, J=4.8 and 1.2 Hz), 8.66 (1H, d,J=2.4 Hz), 8.73 (1H, s), 9.06 (1H, d, J=2.0 Hz). m/z=457 [M+1]⁺.

Example 11N-(6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-yl)benzenesulfonamide

To a solution of6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)-2-(N,N-bis(boc-amino))pyrazine (Intermediate 10) (0.845 g, 1.61 mmol) in DCM (8.05ml) was slowly added TFA (2.48 ml, 32.2 mmol) at 0° C. After stiffingfor 4 hours at room temperature, the reaction mixture was quenched with1N NaOH, and extracted with DCM. The organic layers were dried overMgSO₄, filtered and concentrated in vacuo to give6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine(0.27 g, 52%) as a yellow solid. To a solution of6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyrazin-2-amine(0.1 g, 0.308 mmol) in pyridine (1.542 ml) was slowly addedbenzenesulfonyl chloride (0.050 ml, 0.385 mmol) at 0° C. After stiffingfor 6 hours at room temperature, the reaction mixture was diluted withDCM and quenched with 1N aq. HCl. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was washed with EtOAc and theresulting solid was collected by filtration to giveN-(6-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d.]pyrimidin-6-yl)pyrazin-2-yl)benzenesulfonamide(0.02 g, 14%) as a yellow solid. ¹H-NMR (DMSO-d₆, Varian 400 MHz) δ1.82-1.90 (2H, m), 2.14-2.17 (2H, m), 3.57-3.62 (2H, m), 3.92-4.06 (2H,m), 5.59-5.63 (1H, m), 7.63-7.65 (3H, m), 8.10 (2H, dd, J=2.0, 7.6 Hz),8.43 (1H, s), 8.49 (1H, d, J=8.8 Hz), 8.55 (1H, d, J=8.8 Hz), 8.89 (1H,s), 9.21 (1H, s), 11.96 (1H, s). m/z=465.0 [M+1]⁺.

Example 124-bromo-2-chloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

A mixture of4-bromo-2-chloro-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide(Intermediate 10) (0.0740 g, 0.279 mmol),6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 1) (0.145 g, 0.306 mmol), 1N aq. sodium bicarbonate (0.557ml, 0.557 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.0230 g, 0.0280 mmol) indioxane (1.40 ml) was subjected to microwave irradiation for 1 hour at110° C., and cooled to room temperature. The reaction mixture wasfiltered through a Celite pad and washed with DCM. The combined organiclayers were washed brine, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon SiO₂ (Hex:EtOAc=1:1) to give4-bromo-2-chloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(0.032 g, 20%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.04-2.12 (2H, m), 2.23-2.27 (2H, m), 3.68-3.74 (2H, m), 4.10-4.15 (2H,m), 5.63-5.69 (1H, m), 7.83 (1H, t, J=2.2 Hz), 7.92 (1H, brs), 8.13-8.16(1H, m), 8.22 (1H, d, J=8.0 Hz), 8.34-8.42 (4H, m), 8.84 (1H, s).m/z=577.9 [M+1]⁺.

Example 132-bromo-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridine3-yl)benzenesulfonamide

To a solution of5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine(Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) wasslowly added 2-bromo-4-fluorobenzene-1-sulfonyl chloride (0.0510 g,0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, thereaction mixture was diluted with DCM and quenched with 1N. aq HCl. Thecombined organic layers were washed brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was recrystallized fromEtOAc-Hexane to give2-bromo-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d.]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide(0.0400 g, 46%) as a purple solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.02-2.11 (2H, m), 2.24-2.28 (2H, m), 3.69-3.75 (2H, m), 4.11-4.16 (2H,m), 5.65-5.71 (1H, m), 7.08-7.13 (1H, m), 7.46-7.49 (1H, m), 8.14-8.18(1H, m), 8.22 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=8.8 Hz), 8.55 (1H, s),8.62 (1H, s), 8.84 (1H, s), 9.16 (1H, s). m/z=562.0 [M+1]⁺.

Example 144-bromo-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

To a solution of5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine(Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml) wasslowly added 4-bromo-2-fluorobenzene-1-sulfonyl chloride (0.051 g, 0.186mmol) at 0° C. After stirred for 1 hour at room temperature, thereaction mixture was diluted with DCM and quenched with 1 N. aq HCl. Thecombined organic layers were washed brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was recrystallized fromEtOAc-Hexane to give4-bromo-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide(0.028 g, 32%) as a purple solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H,m), 5.66-5.71 (1H, m), 7.38-7.41 (2H, m), 7.79-7.83 (1H, m), 8.25 (1H,d, J=8.8 Hz), 8.40 (1H, d, J=8.8 Hz), 8.72 (1H, s), 8.85 (1H, s), 9.20(1H, m). m/z=562.1 [M+1]⁺.

Example 154-chloro-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

To a solution of5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine(Intermediate 12) (0.050 g, 0.155 mmol) in pyridine (0.773 ml) wasslowly added 4-chloro-2-fluorobenzene-1-sulfonyl chloride (0.043 g,0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, thereaction mixture was diluted with DCM and quenched with 1N. aq HCl. Thecombined organic layers were washed brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was recrystallized fromEtOAc-Hexane to give4-chloro-2-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide(0.034 g, 43%) as a purple solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.03-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H,m), 5.65-5.71 (1H, m), 7.24 (1H, d, J=8.4 Hz), 7.86-7.90 (1H, m), 8.24(1H, d, J=8.8 Hz), 8.39 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=7.6 Hz), 8.85(1H, s), 9.19 (1H, s). m/z=516.1 [M+1]⁺.

Example 162-chloro-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

To a solution of5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine(Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) wasslowly added 2-chloro-4-fluorobenzene-1-sulfonyl chloride (0.0430 g,0.186 mmol) at 0° C. After stirred for 1 hour at room temperature, thereaction mixture was diluted with DCM and quenched with 1N. aq HCl. Thecombined organic layers were washed brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was recrystallized fromEtOAc-Hexane to give2-chloro-4-fluoro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzene-sulfonamide(0.0500 g, 63%) as a purple solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.02-2.11 (2H, m), 2.23-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H,m), 5.65-5.70 (1H, m), 7.04-7.09 (1H, m), 7.26-7.28 (2H, m), 8.11-8.15(1H, m), 8.22 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8 Hz), 8.54 (1H, s),8.60 (1H, s), 9.16 (1H, s). m/z=516.1 [M+1]⁺.

Example 172,4-dibromo-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

To a solution of5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine(Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) wasslowly added 2,4-dibromobenzene-1-sulfonyl chloride (0.0620 g, 0.186mmol) at 0° C. After stirred for 1 hour at room temperature, thereaction mixture was diluted with DCM and quenched with 1N. aq HCl. Thecombined organic layers were washed brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was recrystallized fromEtOAc-Hexane to give2,4-dibromo-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d.]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(0.0550 g, 57%) as a purple solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.03-2.11 (2H, m), 2.24-2.28 (2H, m), 3.70-3.75 (2H, m), 4.11-4.16 (2H,m), 5.65-5.71 (1H, m), 7.53 (1H, dd, J=2.0, 8.4 Hz), 7.90 (1H, d, J=1.6Hz), 7.97 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=8.8Hz), 8.52 (1H, s), 8.59 (1H, d, J=2.8 Hz), 8.84 (1H, s), 9.16 (1H, d,J=2.0 Hz). m/z=622.0 [M+1]⁺.

Example 182,4-dichloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

To a solution of5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-amine(Intermediate 12) (0.0500 g, 0.155 mmol) in pyridine (0.773 ml) wasslowly added 2,4-dichlorobenzene-1-sulfonyl chloride (0.0460 g, 0.186mmol) at 0° C. After stirred for 1 hour at room temperature, thereaction mixture was diluted with DCM and quenched with 1N. aq HCl. Thecombined organic layers were washed brine, dried over anhydrous MgSO₄,filtered and concentrated in vacuo. The residue was recrystallized fromEtOAc-Hexane to give2,4-dichloro-N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d.]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide(0.0340, 41%) as a purple solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.02-2.11 (2H, m), 2.24-2.29 (2H, m), 3.70-3.75 (2H, m), 4.10-4.16 (2H,m), 5.65-5.71 (1H, m), 7.33 (1H, dd, J=1.8, 8.6 Hz), 7.54 (1H, d, J=2.0Hz), 8.05 (1H, d, J=8.8 Hz), 8.20 (1H, d, J=9.2 Hz), 8.36 (1H, d, J=8.8Hz), 8.48-8.55 (2H, m), 8.84 (1H, s), 9.15 (1H, d, J=1.6 Hz). m/z=532.0[M+1]⁺.

Example 19N-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzamide

A mixture ofN-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzamide(Intermediate 13) (0.07 g, 0.216 mmol),6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 1) (0.063 g, 0.238 mmol), 1N aq. sodium bicarbonate (0.432ml, 0.432 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.018 g, 0.022 mmol) in dioxane(1.08 ml) was subjected to microwave irradiation for 1 hour at 110° C.,and cooled to room temperature. The reaction mixture was filteredthrough a Celite pad and washed with DCM. The filtrate was concentratedin vacuo. The residue was purified by column chromatography on SiO₂(only EtOAc) to giveN-(5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzamide(0.058 g, 63%) as a pink solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.04-2.11 (2H, m), 2.23-2.27 (2H, m), 3.67-3.73 (2H, m), 4.10-4.15 (2H,m), 5.63-5.70 (1H, m), 7.53-7.56 (2H, m), 7.60-7.63 (1H, m), 7.94 (2H,d, J=7.2 Hz), 8.12 (1H, brs), 8.29 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8Hz), 8.83 (1H, s), 8.91 (1H, d, J=2.8 Hz), 9.01 (1H, t, J=2.2 Hz), 9.20(1H, d, J=2.0 Hz). m/z=428.2 [M+1]⁺.

Example 20N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzamide

A mixture ofN-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzamide(Intermediate 14) (0.100 g, 0.253 mmol),6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine(Intermediate 1) (0.074 g, 0.279 mmol), 1N aq. sodium bicarbonate (0.043g, 0.507 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.021 g, 0.025 mmol) in dioxane(1.26 ml) was subjected to microwave irradiation for 1 hour at 110° C.,and cooled to room temperature. The reaction mixture was filteredthrough a Celite pad and washed with DCM. The combined organic layerswere washed brine, dried over anhydrous MgSO₄, filtered and concentratedin vacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to giveN-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzamide(0.020 g, 16%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ2.05-2.13 (2H, m), 2.23-2.27 (2H, m), 3.70-3.76 (2H, m), 4.11-4.18 (2H,m), 5.65-5.71 (1H, m), 7.00-7.05 (1H, m), 7.10-7.15 (1H, m), 8.25-8.38(3H, m), 8.84 (1H, s), 8.03 (1H, d, J=2.4 Hz), 9.19-9.24 (1H, m), 9.71(1H, d, J=2.4 Hz). m/z=498.0 [M+1]⁺.

Example 21N-(5-(4-(cyclohexylthio)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide

A mixture of 6-chloro-4-(cyclohexylthio)pyrido[3,2-d]pyrimidine(Intermediate 15) (0.12 g, 0.429 mmol),N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (Intermediate 2) (0.12 g, 0.429 mmol), 1 N aq.sodium bicarbonate(0.858 ml, 0.858 mmol) and PdCl₂(dppf)-CH₂Cl₂ (0.035 g, 0.043 mmol) indioxane (2.14 ml) was subjected to microwave irradiation for 1 hour at110° C., and cooled to room temperature. The reaction mixture wasfiltered through a Celite pad and washed with DCM. The residue waspurified by column chromatography on SiO₂ (Hex:EtOAc=1:1) to giveN-(5-(4-(cyclohexylthio)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfon-amide(0.09 g, 89%) as a brown solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ1.26-1.28 (1H, m), 1.34-1.43 (1H, m), 1.52-1.85 (4H, m), 1.85-1.87 (2H,m), 2.19-2.23 (2H, m), 4.12-4.19 (1H, m), 7.48-7.58 (3H, m), 7.92 (2H,d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.32 (1H, d, J=9.2 Hz), 8.41-8.43(2H, m), 8.99 (1H, s), 9.13 (1H, s). m/z=478.1 [M+1]⁺.

Example 22N-(2-chloro-5-(4-(cyclopentyloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of 6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine(Intermediate 16) (0.04 g, 0.160 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 2) (0.083 g, 0.192 mmol), 1 N aq. sodium bicarbonate(0.320 ml, 0.320 mmol) and PdCl₂(dppf)-CH₂Cl₂ (1.31 mg, 1.60 μmol) indioxane (0.8 ml) was subjected to microwave irradiation for 1 hour at110° C., and cooled to room temperature. The reaction mixture wasfiltered through a Celite pad and washed with DCM. The residue waspurified by column chromatography on SiO₂ (Hex:EtOAc=1:1) to giveN-(2-chloro-5-(4-(cyclopentyloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide (0.04 g, 48%) as a white solid. ¹H-NMR (CDCl₃, Varian 400MHz): δ 1.70-1.80 (2H, m), 1.92-2.01 (2H, m), 2.04-2.11 (2H, m),2.13-2.22 (2H, m), 5.79-5.83 (1H, m), 6.92-7.00 (2H, m), 7.46 (1H, s),7.93-7.99 (1H, m), 8.17 (1H, d, J=8.8 Hz), 8.35 (1H, d, J=8.8 Hz), 8.79(1H, s), 8.86 (1H, s), 8.90 (1H, s). m/z=517.9 [M+1]⁺.

Example 23N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)-pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine(0.026 g, 0.098 mmol) (Intermediate 17),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.051 g, 0.118 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.802mg, 0.982 μmol) and sodium bicarbonate (0.196 ml, 0.196 mmol) in dioxane(0.491 ml) was refluxed for 3 hours. After cooling to room temperature,the reaction mixture was filtered through Celite and washed with CH₂Cl₂.The filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on SiO₂ (only EtOAc) to giveN-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.015 g, 29%) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ1.68-1.83 (2H, m), 2.13-2.20 (2H, m), 3.58-3.65 (2H, m), 4.05-4.12 (2H,m), 4.41-4.50 (1H, m), 6.94-7.02 (2H, m), 7.18 (1H, d, J=8.0 Hz),7.84-7.90 (1H, m), 8.09 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=8.4 Hz), 8.65(1H, s), 8.74 (1H, d, J=2.0 Hz), 8.84 (1H, d, J=2.4 Hz). NH peak was notobserved. m/z=533.4 [M+1]⁺.

Example 24N-(2-chloro-5-(4-(cyclopentylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of6-chloro-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,2-d]pyrimidin-4-amine(Intermediate 18) (0.043 g, 0.173 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.089 g, 0.207 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (1.41mg, 1.73 μmol) and 1 N aq. sodium bicarbonate (0.346 ml, 0.346 mmol) indioxane (0.864 ml) subjected to microwave irradiation for 1 hour at 110°C. After cooling to room temperature, the reaction mixture was filteredthrough Celite and washed with CH₂Cl₂. The filtrate was concentrated invacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(cyclo pentylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.046 g, 52%) as a white solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ1.65-1.89 (6H, m), 2.18-2.25 (2H, m), 4.61-4.66 (1H, m), 6.93-7.01 (2H,m), 7.22 (1H, d, J=7.6 Hz), 7.85-7.90 (1H, m), 8.07 (1H, d, J=8.8 Hz),8.21 (1H, d, J=8.8 Hz), 8.66 (1H, s), 8.74 (1H, d, J=2.0 Hz), 8.82 (1H,d, J=2.0 Hz). m/z=517.2 [M+1]⁺.

Example 25N-(2-chloro-5-(4-(cyclobutylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of 6-chloro-N-cyclobutylpyrido[3,2-d]pyrimidin-4-amine(Intermediate 19) (0.050 g, 0.213 mmol),N-(2-chloro-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.110 g, 0.256 mmol), PdCl₂(dppf)-CH₂Cl₂ Adduct (1.74mg, 2.13 μmol) and 1 N aq. sodium bicarbonate (0.426 ml, 0.426 mmol) indioxane (1.00 ml) subjected to microwave irradiation for 1 hour at 110°C. After cooling to room temperature, the reaction mixture was filteredthrough Celite and washed with CH₂Cl₂. The filtrate was concentrated invacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to giveN-(2-chloro-5-(4-(cyclobutylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.087 g, 81%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ1.84-1.95 (2H, m), 2.10-2.20 (2H, m), 2.54-2.62 (2H, m), 4.77-4.87 (1H,m), 6.94-7.02 (2H, m), 7.34 (1H, d, J=8.0 Hz), 7.86-7.92 (1H, m), 8.07(1H, d, J=8.8 Hz), 8.21 (1H, d, J=8.8 Hz), 8.65 (1H, s), 8.73 (1H, d,J=2.4 Hz), 8.84 (1H, d, J=2.4 Hz). m/z=503.2 [M+1]⁺.

Example 26N-(2-chloro-5-(4-(cyclopropylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of 6-chloro-N-cyclopropylpyrido[3,2-d]pyrimidin-4-amine(Intermediate 20) (0.060 g, 0.272 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.141 g, 0.326 mmol), PdCl₂(dppf)-CH₂Cl₂ Adduct (2.221mg, 2.72 μmmol) and 1 N aq. sodium bicarbonate (0.544 ml, 0.544 mmol) indioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110°C. After cooling to room temperature, the reaction mixture was filteredthrough Celite and washed with CH₂Cl₂. The filtrate was concentrated invacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to giveN-(2-chloro-5-(4-(cyclopropylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.070 g, 53%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ0.78-0.82 (2H, m), 1.04-1.09 (2H, m), 3.08-3.13 (1H, m), 6.95-7.02 (2H,m), 7.30 (1H, brs), 7.85-7.91 (1H, m), 8.08 (1H, d, J=8.8 Hz), 8.24 (1H,d, J=8.8 Hz), 8.67 (1H, d, J=2.0 Hz), 8.76 (1H, s), 8.81 (1H, d, J=2.0Hz). m/z=489.2 [M+1]⁺.

Example 27N-(2-chloro-5-(4-(3,5-dimethylisoxazol-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture ofN-(6-chloropyrido[3,2-d]pyrimidin-4-yl)-3,5-dimethylisoxazol-4-amine(Intermediate 21) (0.040 g, 0.145 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.069 g, 0.160 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.012g, 0.015 μmol) and 1 N aq. sodium bicarbonate (0.290 ml, 0.290 mmol) indioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110°C. After cooling to room temperature, the reaction mixture was filteredthrough Celite and washed with CH₂Cl₂. The filtrate was concentrated invacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to giveN-(2-chloro-5-(4-(3,5-dimethylisoxazol-4-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.021 g, 27%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 2.30(3H, s), 2.45 (3H, s), 6.89-7.05 (2H, m), 7.27 (1H, s), 7.79-7.92 (1H,m), 8.20 (1H, d, J=8.8 Hz), 8.26 (1H, s), 8.36 (1H, d, J=8.8 Hz), 8.73(1H, s), 8.76 (1H, s), 8.89 (1H, s). m/z=544.1 [M+1]⁺.

Example 28N-(2-chloro-5-(4-(6-methoxypyridin-3-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of6-chloro-N-(6-methoxypyridin-3-yl)pyrido[3,2-d]pyrimidin-4-amine(Intermediate 22) (0.040 g, 0.139 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.066 g, 0.153 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (0.011g, 0.014 mmol) and 1 N aq. sodium bicarbonate (0.278 ml, 0.278 mmol) indioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110°C. After cooling to room temperature, the reaction mixture was filteredthrough Celite and washed with CH₂Cl₂. The filtrate was concentrated invacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to giveN-(2-chloro-5-(4-(6-methoxypyridin-3-ylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.024 g, 31%) as a yellow solid. ¹H-NMR (DMSO-d₆, Varian 400 MHz) δ3.89 (3H, s), 6.94 (3H, s), 6.89-7.05 (1H, d, J=8.4 Hz), 7.17-7.28 (1H,m), 7.50-7.65 (1H, m), 7.74-7.86 (1H, m), 8.17 (1H, dd, J=2.4, 8.8 Hz),8.33 (1H, d, J=8.8 Hz), 8.36 (1H, d, J=8.8 Hz), 8.57 (1H, d, J=8.8 Hz),8.62 (2H, s), 8.82 (1H, s), 9.48 (1H, s), 10.33 (1H, s), 10.98 (1H, brs). m/z=556.2 [M+1]⁺.

Example 29N-(2-chloro-5-(4-(4-(trifluoromethoxy)phenylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide

A mixture of6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine(Intermediate 23) (0.050 g, 0.147 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.070 g, 0.161 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (5.99mg, 7.34 mop and 1 N aq. sodium bicarbonate (0.294 ml, 0.294 mmol) indioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110°C. After cooling to room temperature, the reaction mixture was filteredthrough Celite and washed with CH₂Cl₂. The filtrate was concentrated invacuo. The residue was purified by column chromatography on SiO₂(Hex:EtOAc=1:1) to giveN-(2-chloro-5-(4-(4-(trifluoromethoxy)phenylamino)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzenesulfonamide(0.049 g, 55%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ6.88-7.05 (2H, m), 7.34 (2H, d, J=8.8 Hz), 7.85-7.95 (1H, m), 8.05-8.10(2H, m), 8.19 (1H, d, J=8.8 Hz), 8.34 (1H, d, J=8.4 Hz), 8.84 (1H, s),8.85-8.90 (2H, m), 9.26 (1H, br s). 1NH was not detected. m/z=609.1[M+1]⁺.

Example 30 tert-butyl4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate

A mixture of tert-butyl4-(6-chloropyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate(Intermediate 24) (0.050 g, 0.137 mmol),N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-yl)-2,4-difluorobenzenesulfonamide(Intermediate 3) (0.065 g, 0.151 mmol), PdCl₂(dppf)-CH₂Cl₂Adduct (5.61mg, 6.87 μmol) and 1 N aq. sodium bicarbonate (0.275 ml, 0.275 mmol) indioxane (1.40 ml) subjected to microwave irradiation for 1 hour at 110°C. After cooling to room temperature, the reaction mixture was filteredthrough Celite and washed with CH₂Cl₂. The filtrate was concentrated invacuo. The residue was purified by prep TLC (Hex:EtOAc=1:2) to givetert-butyl4-(6-(6-chloro-5-(2,4-difluorophenylsulfonamido)pyridin-3-yl)pyrido[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate(3.90 mg, 4.5%) as a yellow solid. ¹H-NMR (CDCl₃, Varian 400 MHz) δ 1.48(9H, s), 1.55-1.72 (2H, m), 2.05-2.22 (2H, m), 2.92-3.12 (2H, m),4.02-4.25 (2H, m), 4.30-4.48 (1H, m), 6.90-7.04 (2H, m), 7.14 (1H, J=8.0Hz), 7.80-7.92 (1H, m), 8.07 (1H, d, J=8.8 Hz), 8.22 (1H, d, J=8.8 Hz),8.69 (1H, s), 8.70 (1H, br s), 8.79 (1H, br s). m/z=632.2 [M+1]⁺¹.

Biological Activity Materials and Preparation of Reagents

The PI3 Kinase Activity/Inhibitor Assay Kit was purchased fromMillipore. The dimethylsulfoxide was purchased from Sigma-Aldrich.

Assay Principle

The PI3 Kinase Activity/Inhibitor Assay is a competitive assay used forthe fast and sensitive quantitation of activity of the four class I PI3kinases (p110 α, β, γ, δ). The PI3 Kinase Activity/Inhibitor Assay workson the principle that PI3 Kinase phosphorylates P1(3,4)P2 (PIP2),converting it to PI(3,4,5)P3 (PIP3). The PH domain of the protein GRP-1binds PIP3 with high affinity and specificity. The kit includes thisrecombinant protein that is used as the capture protein. This proteinbinds to the glutathione plate and captures either the PIP3 generated aspart of the kinase reaction or the biotinylated-PIP3 tracer included inthe kit. The captured biotinylated-PIP3 is detected usingstreptavidin-HRP conjugate and a colorimetric read out (OD 450). Thelower the signal, the higher the PI3 Kinase activity.

Assay Protocol

PI3-Kinase included in the Kit was diluted at the ratio of 1:10 withdistilled water and stored on ice. The compound was prepared by dilutingthe stock compound to 100× of the final concentration and then dilutedagain at the ratio of 1:50 to make 2× of the final concentration withdistilled water.

The prepared PI3-Kinase (5 μL/well) and the compound (5 μL/well) wereadded to Glutathione-Coated Plate and pre-incubated at room temperaturefor 10 minutes. After adding 5 μL of 5× Kinase reaction buffer per well,PIP2 was diluted at the ratio of 1:20 with distilled water and 5 μL wereadded into each well. Distilled water was added up to 25 μL, and thereaction mixture was incubated at room temperature for an hour.Biotinylated-PIP3 was diluted at the ratio of 1:18 with 1×TBS solutionand 25 μL of the mixture were put in each well excluding the buffercontrol well. GRP1-GST was diluted at the ratio of 1:1000 with 1×TBSsolution and 50 μL of it was added to every well. The mixture wasincubated at room temperature for an hour.

After removing the solution contained in the wells, the wells werewashed 4 times with 200 μL of 1×TBST. SA-HRP was diluted at the ratio of1:2000 with 1×TBST, then 50 μL of it was added into every well andincubated at room temperature for an hour. Again after removing thesolution, they were washed 5 times by adding 200 μL of 1×TBST to eachwell. 100 μL of TMB solution was added to every well. The plate wasdeveloped in the dark for 5-20 minutes. As blue color appeared, thereaction was stopped by adding 100 μL of stop solution to every well,and the plate was read at 450 nm with ELISA Reader (TECAN).

Data Analysis

For the calculation of relative percentage to biotinylated-PIP3, we takethe direct absorbance at 450 nm (A450) and set the positiveBiotinylated-PIP3 wells as 100 percentage. All the other signals aredivided by the Biotinylated-PIP3 average, and multiplied by 100 to showthe relative percentage to the positive signal.

Relative % to B-PIP3=(A450 of samples include buffer, kinase &inhibitors/A450 of Biotinylated-PIP3 average)×100

IC₅₀ values were calculated from the values read at 450 nm by usingGraphpad Prism 5 software.

Biological Data for Select Compounds

Select compounds prepared as described above were assayed according tothe biological procedures described herein. The results are given in thetable below:

IC₅₀ (uM) Structure PI3Kα PI3Kγ PI3Kδ

<10 <1 <10

<10 <1 <10

<1 <1 <1

<1 <10 <1

<10 <10 <10

<10 <10 <10

1. A compound of formula I,

Wherein X is C or O or N or S; Y is C or N; R₁ is selected from thegroup consisting of acyl, amino, substituted amino, C1-C6alkyl,substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl,C3-C7heterocycloalkyl, substituted C3-C7 heterocycloalkyl, alkylcarboxy,arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl,arylalkyl, substituted arylalkyl, arylcycloalkyl, substitutedarylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano,nitro; R₂ is selected from the group consisting of hydrogen, halogen,acyl, amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl,C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl, C3-7Cheterocycloalkyl,substituted C3-C7heterocycloalkyl, alkylcarboxy, arylamino, aryl,substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl,substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl,heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro, alkoxy,C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy,C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy, acyloxy,aryloxy; R₃═NR_(4′)SO₂R₄, SO₂NR_(4′)R₄, NR_(4′)COR₄, CONR_(4′)R₄,NR_(4′)CONHR₄; R₄ is selected from the group consisting of alkyl,substituted alkyl, amino, halo, C3-C7cycloalkyl, substitutedC3-C7cycloalkyl, C3-C7heterocycloalkyl, substitutedC3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl andsubstituted heteroaryl; R_(4′) is H or C1-C6 alkyl; R₅ is selected fromthe group consisting of hydrogen, halogen, C1-C6alkyl; R₆ is selectedfrom the group consisting of hydrogen, halogen, acyl, alkoxy, amino,substituted amino, arylamino, C1-C6alkyl, substituted C1-C6 alkyl,C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl,substituted C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl,and substituted heteroaryl; n is 0 or 1; m is 0 or 1; and/or apharmaceutically acceptable salt, solvate, polymorph, tautomer orprodrug thereof.
 2. A compound according to claim 1 which is selectedfrom the following

or a pharmaceutically acceptable salt, solvate, polymorph, ester,tautomer or prodrug thereof.
 3. A pharmaceutical composition comprisinga pharmaceutically effective amount of a compound of any of claims 1 to2 or a pharmaceutically acceptable salt, solvate, poly-morph, ester,tautomer or prodrug thereof, and a pharmaceutically acceptable carrier.4. Use of a compound of any of claims 1 to 2 or a pharmaceuticallyacceptable salt, solvate, poly-morph, ester, tautomer or prodrug thereofin the preparation of a pharmaceutical composition for inhibiting PI3Kenzyme.
 5. Use of a compound of any of claims 1 to 2 or apharmaceutically acceptable salt, solvate, poly-morph, ester, tautomeror prodrug thereof in the preparation of a pharmaceutical compositionfor the treatment or prophylaxis of a PI3K mediated disorder or disease6. Use of a compound of any of claims 1 to 2 or a pharmaceuticallyacceptable salt, solvate, poly-morph, ester, tautomer or prodrug thereofin the preparation of a pharmaceutical composition for the treatment orprophylaxis of proliferative disorders.
 7. Use of claim 6, wherein theproliferative disorders are selected from the group consisting ofinflammatory diseases, cancer, cardiovascular diseases, allergy, asthmaand autoimmune disorders.